Elizabeth Mechcatie

Candesartan's heart failure indication has been expanded by the Food and Drug Administration to include patients who are on ACE inhibitor therapy.

The angiotensin receptor blocker (ARB) was approved for a narrower heart failure indication in February, for patients with New York Heart Association (NYHA) class II-IV disease and a left ventricular ejection fraction (LVEF) of 40% or less to reduce cardiovascular death and heart failure hospitalizations, based largely on the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial, in which cardiovascular death or heart failure hospitalization, the primary end point, was reduced by 23% in those on candesartan, compared with those on placebo.

In May, the FDA approved the addition of the following statement to the heart failure indication in the drug's label: “Atacand also has an added effect on these outcomes when used with an ACE inhibitor.”

Candesartan, marketed as Atacand by AstraZeneca, was approved for treating hypertension in 1998. It is the first ARB approved for use with an ACE inhibitor for treating heart failure.

The latest approval was based on the results of the CHARM-Added trial, which showed that candesartan “adds a meaningful and important additional clinical benefit on top of other proven treatments, including β-blockers and ACE inhibitors,” Christopher Granger, M.D., director of the cardiac care unit at Duke University, Durham, N.C., and a member of the CHARM executive committee, said in an interview.

The relative risk of cardiovascular mortality or heart failure hospitalization was reduced by 15% in those on candesartan during a median follow-up of 41 months in CHARM-Added, which compared candesartan to placebo in 2,548 patients with NYHA class II-IV heart failure and an LVEF of 40% or less who were on an ACE inhibitor and standard therapy. Benefits were also seen in patients treated with β-blockers, suggesting there were no adverse interactions between β-blockers, candesartan, and ACE inhibitors.

Improved quality of life was also seen in the study, said Dr. Granger, who was a consultant to AstraZeneca for the FDA's cardiovascular and renal drugs advisory committee meeting in February, where the panel unanimously recommended approval of candesartan for this population of patients on an ACE inhibitor (CARDIOLOGY NEWS, April 2005, p. 10).

The recommended starting dose of candesartan for patients with heart failure is 4 mg/day, with a target dose of 32 mg once daily, achieved by doubling the dose about every 2 weeks, as tolerated.

In the CHARM studies, rates of hypotension, abnormal renal function, and hyperkalemia were higher in those on candesartan, as expected, due to a greater degree of renin-angiotensin-aldosterone system inhibition. Clinicians should monitor for hyperkalemia and renal insufficiency, especially when starting and titrating treatment, Dr. Granger advised.

Candesartan's heart failure indication has been expanded by the Food and Drug Administration to include patients who are on ACE inhibitor therapy.

The angiotensin receptor blocker (ARB) was approved for a narrower heart failure indication in February, for patients with New York Heart Association (NYHA) class II-IV disease and a left ventricular ejection fraction (LVEF) of 40% or less to reduce cardiovascular death and heart failure hospitalizations, based largely on the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial, in which cardiovascular death or heart failure hospitalization, the primary end point, was reduced by 23% in those on candesartan, compared with those on placebo.

In May, the FDA approved the addition of the following statement to the heart failure indication in the drug's label: “Atacand also has an added effect on these outcomes when used with an ACE inhibitor.”

Candesartan, marketed as Atacand by AstraZeneca, was approved for treating hypertension in 1998. It is the first ARB approved for use with an ACE inhibitor for treating heart failure.

The latest approval was based on the results of the CHARM-Added trial, which showed that candesartan “adds a meaningful and important additional clinical benefit on top of other proven treatments, including β-blockers and ACE inhibitors,” Christopher Granger, M.D., director of the cardiac care unit at Duke University, Durham, N.C., and a member of the CHARM executive committee, said in an interview.

The relative risk of cardiovascular mortality or heart failure hospitalization was reduced by 15% in those on candesartan during a median follow-up of 41 months in CHARM-Added, which compared candesartan to placebo in 2,548 patients with NYHA class II-IV heart failure and an LVEF of 40% or less who were on an ACE inhibitor and standard therapy. Benefits were also seen in patients treated with β-blockers, suggesting there were no adverse interactions between β-blockers, candesartan, and ACE inhibitors.

Improved quality of life was also seen in the study, said Dr. Granger, who was a consultant to AstraZeneca for the FDA's cardiovascular and renal drugs advisory committee meeting in February, where the panel unanimously recommended approval of candesartan for this population of patients on an ACE inhibitor (CARDIOLOGY NEWS, April 2005, p. 10).

The recommended starting dose of candesartan for patients with heart failure is 4 mg/day, with a target dose of 32 mg once daily, achieved by doubling the dose about every 2 weeks, as tolerated.

In the CHARM studies, rates of hypotension, abnormal renal function, and hyperkalemia were higher in those on candesartan, as expected, due to a greater degree of renin-angiotensin-aldosterone system inhibition. Clinicians should monitor for hyperkalemia and renal insufficiency, especially when starting and titrating treatment, Dr. Granger advised.

Candesartan's heart failure indication has been expanded by the Food and Drug Administration to include patients who are on ACE inhibitor therapy.

The angiotensin receptor blocker (ARB) was approved for a narrower heart failure indication in February, for patients with New York Heart Association (NYHA) class II-IV disease and a left ventricular ejection fraction (LVEF) of 40% or less to reduce cardiovascular death and heart failure hospitalizations, based largely on the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial, in which cardiovascular death or heart failure hospitalization, the primary end point, was reduced by 23% in those on candesartan, compared with those on placebo.

In May, the FDA approved the addition of the following statement to the heart failure indication in the drug's label: “Atacand also has an added effect on these outcomes when used with an ACE inhibitor.”

Candesartan, marketed as Atacand by AstraZeneca, was approved for treating hypertension in 1998. It is the first ARB approved for use with an ACE inhibitor for treating heart failure.

The latest approval was based on the results of the CHARM-Added trial, which showed that candesartan “adds a meaningful and important additional clinical benefit on top of other proven treatments, including β-blockers and ACE inhibitors,” Christopher Granger, M.D., director of the cardiac care unit at Duke University, Durham, N.C., and a member of the CHARM executive committee, said in an interview.

The relative risk of cardiovascular mortality or heart failure hospitalization was reduced by 15% in those on candesartan during a median follow-up of 41 months in CHARM-Added, which compared candesartan to placebo in 2,548 patients with NYHA class II-IV heart failure and an LVEF of 40% or less who were on an ACE inhibitor and standard therapy. Benefits were also seen in patients treated with β-blockers, suggesting there were no adverse interactions between β-blockers, candesartan, and ACE inhibitors.

Improved quality of life was also seen in the study, said Dr. Granger, who was a consultant to AstraZeneca for the FDA's cardiovascular and renal drugs advisory committee meeting in February, where the panel unanimously recommended approval of candesartan for this population of patients on an ACE inhibitor (CARDIOLOGY NEWS, April 2005, p. 10).

The recommended starting dose of candesartan for patients with heart failure is 4 mg/day, with a target dose of 32 mg once daily, achieved by doubling the dose about every 2 weeks, as tolerated.

In the CHARM studies, rates of hypotension, abnormal renal function, and hyperkalemia were higher in those on candesartan, as expected, due to a greater degree of renin-angiotensin-aldosterone system inhibition. Clinicians should monitor for hyperkalemia and renal insufficiency, especially when starting and titrating treatment, Dr. Granger advised.

WASHINGTON — The prevalence of urinary tract infections in women resistant to standard treatment has been increasing, but there are indications that the increase has begun to level off, Patricia D. Brown, M.D., said at an update on sexually transmitted infections.

Emerging uropathogenic Escherichia coli antimicrobial resistance—particularly to the front-line, first choice treatment of urinary tract infections (UTIs), trimethoprim-sulfamethoxazole (TMP-SMX)—has been documented worldwide. However, much of the data are based on passive surveillance, which can overestimate prevalence, because women with acute, uncomplicated UTIs often do not have cultures performed, so these cases are not reported, said Dr. Brown of Wayne State University, Detroit.

Women who do have a culture have complicated disease and fail treatment, leading to overestimates of true prevalence, she added. Still, passive surveillance can provide information on trends.

In the United States, active surveillance has been conducted in specific geographic areas, where the true prevalence may not reflect that of other geographic areas, Dr. Brown said at the meeting, sponsored by OB.GYN. NEWS, FAMILY PRACTICE NEWS, and Boston University.

Recent studies indicate that TMP-SMX resistance “may be leveling off” after peaking at about 25%, which is probably because of the reduced use of this treatment, she said.

But as the use of TMP-SMX for UTIs has decreased, resistance to other antimicrobial agents has been increasing.

In 890 isolates from women with UTIs in the United States who were a part of the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study, the prevalence of TMP-SMX resistance was about 23%. Resistance to ampicillin was 38%, and resistance to levofloxacin was nearly 7%.

As the use of TMP-SMX has dropped, the use of fluoroquinolones has increased, Dr. Brown said, noting that rates of resistance to β-lactams such as ampicillin have been high for some time.

In the NAUTICA study, resistance to nitrofurantoin was only 1.8%, which she said was “remarkable,” considering that it has been available for about 50 years. But that rate has probably remained so low because the agent has several mechanisms of action and is indicated only for cystitis, she noted.

There are several clinical implications of these resistance trends: In treatment studies of pyelonephritis, antimicrobial resistance has clearly been shown to increase the risks of both clinical and microbiologic failure, she said. She cited a retrospective cohort study of women with acute uncomplicated cystitis, in which the risk of clinical failure was 45.4%, and a prospective study in Israel of empiric TMP-SMX in an area where the prevalence of resistance was high, in which the risk of clinical failure was 46%.

Identifying risk factors for resistance can help guide antibiotic choice, she said, referring to the difficulty facing clinicians, who usually do not have access to resistance trends and who likely will be given an overestimate of resistance if they call their local microbiology lab.

Results of retrospective case-control studies have identified potential risk factors for infection with a uropathogen resistant to TMP-SMX. Two risk factors found in every such study include recent antibiotic use and recent hospitalization, she said.

Recent travel to underdeveloped countries has been identified as an independent risk factor in several studies.

The standard treatment of uncomplicated cystitis is 3 days of double-strength formulations of TMP-SMX twice a day. Avoid empiric treatment with TMP-SMX in patients who have recently been hospitalized or have taken antibiotics in the previous 3 months, she said.

Alternative treatments for those with risk factors for resistance are a 7-day course of nitrofurantoin or a 3-day course of a fluoroquinolone. The major drawback of the former is that a full-week course is necessary.

As for fluoroquinolones, ciprofloxacin is available in generic formulations, so it is less expensive. The Food and Drug Administration has approved gatifloxacin as a single-dose treatment for uncomplicated cystitis. One fluoroquinolone that should not be used for UTI is moxifloxacin, which is indicated for respiratory infections, because treatment results in low levels of the drug in the urinary tract.

A single dose of fosfomycin is another alternative, but is considered a second-line treatment because the efficacy is not that high and it is expensive.

One benefit, however, is that resistance to this agent appears to be low, Dr. Brown said.

Short-course treatment is not appropriate for complicated cystitis, which should be treated with a 7-day course of therapy, she said. Culture all patients, and adjust treatment based on susceptibility data, she said.

As many as 25% of women with acute cystitis can develop frequent, recurrent UTIs, which are reinfections, not relapses. (Fewer than 5% of these women have a correctable structural or functional abnormality of the urinary tract.) Management strategies include daily or postcoital prophylaxis and self-start therapy for women concerned about developing a UTI when they are away from home, she added.

Dr. Brown said that he considers topical estrogen for postmenopausal women who have recurrent UTIs.

WASHINGTON — The prevalence of urinary tract infections in women resistant to standard treatment has been increasing, but there are indications that the increase has begun to level off, Patricia D. Brown, M.D., said at an update on sexually transmitted infections.

Emerging uropathogenic Escherichia coli antimicrobial resistance—particularly to the front-line, first choice treatment of urinary tract infections (UTIs), trimethoprim-sulfamethoxazole (TMP-SMX)—has been documented worldwide. However, much of the data are based on passive surveillance, which can overestimate prevalence, because women with acute, uncomplicated UTIs often do not have cultures performed, so these cases are not reported, said Dr. Brown of Wayne State University, Detroit.

Women who do have a culture have complicated disease and fail treatment, leading to overestimates of true prevalence, she added. Still, passive surveillance can provide information on trends.

In the United States, active surveillance has been conducted in specific geographic areas, where the true prevalence may not reflect that of other geographic areas, Dr. Brown said at the meeting, sponsored by OB.GYN. NEWS, FAMILY PRACTICE NEWS, and Boston University.

Recent studies indicate that TMP-SMX resistance “may be leveling off” after peaking at about 25%, which is probably because of the reduced use of this treatment, she said.

But as the use of TMP-SMX for UTIs has decreased, resistance to other antimicrobial agents has been increasing.

In 890 isolates from women with UTIs in the United States who were a part of the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study, the prevalence of TMP-SMX resistance was about 23%. Resistance to ampicillin was 38%, and resistance to levofloxacin was nearly 7%.

As the use of TMP-SMX has dropped, the use of fluoroquinolones has increased, Dr. Brown said, noting that rates of resistance to β-lactams such as ampicillin have been high for some time.

In the NAUTICA study, resistance to nitrofurantoin was only 1.8%, which she said was “remarkable,” considering that it has been available for about 50 years. But that rate has probably remained so low because the agent has several mechanisms of action and is indicated only for cystitis, she noted.

There are several clinical implications of these resistance trends: In treatment studies of pyelonephritis, antimicrobial resistance has clearly been shown to increase the risks of both clinical and microbiologic failure, she said. She cited a retrospective cohort study of women with acute uncomplicated cystitis, in which the risk of clinical failure was 45.4%, and a prospective study in Israel of empiric TMP-SMX in an area where the prevalence of resistance was high, in which the risk of clinical failure was 46%.

Identifying risk factors for resistance can help guide antibiotic choice, she said, referring to the difficulty facing clinicians, who usually do not have access to resistance trends and who likely will be given an overestimate of resistance if they call their local microbiology lab.

Results of retrospective case-control studies have identified potential risk factors for infection with a uropathogen resistant to TMP-SMX. Two risk factors found in every such study include recent antibiotic use and recent hospitalization, she said.

Recent travel to underdeveloped countries has been identified as an independent risk factor in several studies.

The standard treatment of uncomplicated cystitis is 3 days of double-strength formulations of TMP-SMX twice a day. Avoid empiric treatment with TMP-SMX in patients who have recently been hospitalized or have taken antibiotics in the previous 3 months, she said.

Alternative treatments for those with risk factors for resistance are a 7-day course of nitrofurantoin or a 3-day course of a fluoroquinolone. The major drawback of the former is that a full-week course is necessary.

As for fluoroquinolones, ciprofloxacin is available in generic formulations, so it is less expensive. The Food and Drug Administration has approved gatifloxacin as a single-dose treatment for uncomplicated cystitis. One fluoroquinolone that should not be used for UTI is moxifloxacin, which is indicated for respiratory infections, because treatment results in low levels of the drug in the urinary tract.

A single dose of fosfomycin is another alternative, but is considered a second-line treatment because the efficacy is not that high and it is expensive.

One benefit, however, is that resistance to this agent appears to be low, Dr. Brown said.

Short-course treatment is not appropriate for complicated cystitis, which should be treated with a 7-day course of therapy, she said. Culture all patients, and adjust treatment based on susceptibility data, she said.

As many as 25% of women with acute cystitis can develop frequent, recurrent UTIs, which are reinfections, not relapses. (Fewer than 5% of these women have a correctable structural or functional abnormality of the urinary tract.) Management strategies include daily or postcoital prophylaxis and self-start therapy for women concerned about developing a UTI when they are away from home, she added.

Dr. Brown said that he considers topical estrogen for postmenopausal women who have recurrent UTIs.

WASHINGTON — The prevalence of urinary tract infections in women resistant to standard treatment has been increasing, but there are indications that the increase has begun to level off, Patricia D. Brown, M.D., said at an update on sexually transmitted infections.

Emerging uropathogenic Escherichia coli antimicrobial resistance—particularly to the front-line, first choice treatment of urinary tract infections (UTIs), trimethoprim-sulfamethoxazole (TMP-SMX)—has been documented worldwide. However, much of the data are based on passive surveillance, which can overestimate prevalence, because women with acute, uncomplicated UTIs often do not have cultures performed, so these cases are not reported, said Dr. Brown of Wayne State University, Detroit.

Women who do have a culture have complicated disease and fail treatment, leading to overestimates of true prevalence, she added. Still, passive surveillance can provide information on trends.

In the United States, active surveillance has been conducted in specific geographic areas, where the true prevalence may not reflect that of other geographic areas, Dr. Brown said at the meeting, sponsored by OB.GYN. NEWS, FAMILY PRACTICE NEWS, and Boston University.

Recent studies indicate that TMP-SMX resistance “may be leveling off” after peaking at about 25%, which is probably because of the reduced use of this treatment, she said.

But as the use of TMP-SMX for UTIs has decreased, resistance to other antimicrobial agents has been increasing.

In 890 isolates from women with UTIs in the United States who were a part of the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study, the prevalence of TMP-SMX resistance was about 23%. Resistance to ampicillin was 38%, and resistance to levofloxacin was nearly 7%.

As the use of TMP-SMX has dropped, the use of fluoroquinolones has increased, Dr. Brown said, noting that rates of resistance to β-lactams such as ampicillin have been high for some time.

In the NAUTICA study, resistance to nitrofurantoin was only 1.8%, which she said was “remarkable,” considering that it has been available for about 50 years. But that rate has probably remained so low because the agent has several mechanisms of action and is indicated only for cystitis, she noted.

There are several clinical implications of these resistance trends: In treatment studies of pyelonephritis, antimicrobial resistance has clearly been shown to increase the risks of both clinical and microbiologic failure, she said. She cited a retrospective cohort study of women with acute uncomplicated cystitis, in which the risk of clinical failure was 45.4%, and a prospective study in Israel of empiric TMP-SMX in an area where the prevalence of resistance was high, in which the risk of clinical failure was 46%.

Identifying risk factors for resistance can help guide antibiotic choice, she said, referring to the difficulty facing clinicians, who usually do not have access to resistance trends and who likely will be given an overestimate of resistance if they call their local microbiology lab.

Results of retrospective case-control studies have identified potential risk factors for infection with a uropathogen resistant to TMP-SMX. Two risk factors found in every such study include recent antibiotic use and recent hospitalization, she said.

Recent travel to underdeveloped countries has been identified as an independent risk factor in several studies.

The standard treatment of uncomplicated cystitis is 3 days of double-strength formulations of TMP-SMX twice a day. Avoid empiric treatment with TMP-SMX in patients who have recently been hospitalized or have taken antibiotics in the previous 3 months, she said.

Alternative treatments for those with risk factors for resistance are a 7-day course of nitrofurantoin or a 3-day course of a fluoroquinolone. The major drawback of the former is that a full-week course is necessary.

As for fluoroquinolones, ciprofloxacin is available in generic formulations, so it is less expensive. The Food and Drug Administration has approved gatifloxacin as a single-dose treatment for uncomplicated cystitis. One fluoroquinolone that should not be used for UTI is moxifloxacin, which is indicated for respiratory infections, because treatment results in low levels of the drug in the urinary tract.

A single dose of fosfomycin is another alternative, but is considered a second-line treatment because the efficacy is not that high and it is expensive.

One benefit, however, is that resistance to this agent appears to be low, Dr. Brown said.

Short-course treatment is not appropriate for complicated cystitis, which should be treated with a 7-day course of therapy, she said. Culture all patients, and adjust treatment based on susceptibility data, she said.

As many as 25% of women with acute cystitis can develop frequent, recurrent UTIs, which are reinfections, not relapses. (Fewer than 5% of these women have a correctable structural or functional abnormality of the urinary tract.) Management strategies include daily or postcoital prophylaxis and self-start therapy for women concerned about developing a UTI when they are away from home, she added.

Dr. Brown said that he considers topical estrogen for postmenopausal women who have recurrent UTIs.

Prospects for the eventual return of the multiple sclerosis treatment natalizumab (Tysabri) became more uncertain when a second case of progressive multifocal leukoencephalopathy was confirmed in a patient who had been treated with the drug for more than 2 years, in combination with interferon beta-1a.

On Feb. 28, Elan Corporation and Biogen Idec announced that marketing of the monoclonal antibody, which had received U.S. Food and Drug Administration approval months earlier for relapsing forms of multiple sclerosis (MS), was being suspended because of one confirmed case of progressive multifocal leukoencephalopathy (PML) in a patient who had died and a second suspected case.

In early March, the companies announced that this second case had also been confirmed. The patient was a woman who, like the first patient, had been on the drug for over 2 years in combination with interferon beta-1a (Avonex), another Biogen product that was approved for MS in 1996.

One patient had been treated for 38 months, the other, 27 months. No cases of PML, a rare, usually fatal, progressive demyelinating central nervous system disease, have been reported in patients with MS who have used natalizumab as monotherapy, or in the Crohn's disease or rheumatoid arthritis trials. In addition, no cases of PML have been reported in patients who have been treated with interferon beta-1a monotherapy since its approval in 1996.

In March, the FDA suspended clinical trials of all MS drugs that are in the same class as natalizumab, as a precaution. One drug affected is 683699, an investigational agent developed by European drugmaker GlaxoSmithKline, which was in phase II trials at the time of the FDA action.

Since approval in late November, about 5,000 people have been treated with natalizumab, but most had received only a few doses since it is administered intravenously once every 4 weeks. About 3,000 patients had received natalizumab in clinical trials, largely for MS. The drug was also stopped in patients enrolled in smaller trials of rheumatoid arthritis and Crohn's disease.

In the companies' efforts to determine the association between natalizumab and PML, and to determine whether MS patients who may be at risk for developing PML can be identified, the two companies are working with a panel of PML experts, and are reviewing clinical information and MRI scans of all patients in clinical trials. These patients will also undergo physical exams, and will undergo MRIs to look for early signs of PML.

The companies hope to find “a path back for this drug,” Al Sandrock, M.D., vice president of medical research at Biogen Idec, said during a Webcast sponsored by the National MS Society in New York City after the suspension. He would not speculate on when or if it would become available again, but added that the companies recognize the benefits of the drug. Within days of learning about the two cases, the companies decided to suspend marketing, “to step back and assess the risk.”

In a “dear health care professional” letter, the companies advised physicians to evaluate their patients who have taken natalizumab for signs of PML, and to report any suspected cases. Impaired cognition, cortical blindness, and hemiparesis are usually among the presenting symptoms, and characteristic lesions are usually present on MRI scans.

PML primarily affects those who are immunocompromised, with the vast majority of cases today seen in patients with AIDs or HIV. It is caused by the activation of a human polyomavirus, JC virus, which is latent in more than 80% of healthy adults, and can be similar in presentation to MS although the cause of demyelination differs.

The FDA approved natalizumab for reducing the frequency of exacerbations in people with relapsing forms of MS. The accelerated approval was based on the first year of efficacy and safety data from two ongoing international trials of over 2,000 patients, under the condition that the companies complete the second year of the trials.

During the first year of treatment, those on monotherapy had 66% fewer relapses than those on placebo, and in the second trial, those on the combination had 54% fewer relapses than those on interferon beta-1a alone. No major safety concerns were raised in these studies.

During the National MS Society Webcast, Aaron Miller, M.D., said that although PML and MS are both demyelinating diseases, the mechanisms of demyelination are different and PML is “not at all related to MS,” he said. With PML, the virus destroys oligodendrocytes in the brain, which make myelin; but in most if not all cases of MS, an inflammatory process destroys myelin, said Dr. Miller, chief medical officer of the society and medical director of the Corinne Goldsmith Dickinson Center for MS, at Mt. Sinai Medical Center, New York.

Dr. Miller described the PML cases and subsequent suspension of the drug from marketing as “a great tragedy for the entire MS community. We certainly hope that after the dust has cleared, we will be able to find a way to safely bring this drug back to patients,” he said, but added, “that remains to be seen.”

The FDA's public health advisory regarding natalizumabcan be found at www.fda.gov/cder/drug/advisory/natalizumab.htmwww.elan.com

Prospects for the eventual return of the multiple sclerosis treatment natalizumab (Tysabri) became more uncertain when a second case of progressive multifocal leukoencephalopathy was confirmed in a patient who had been treated with the drug for more than 2 years, in combination with interferon beta-1a.

On Feb. 28, Elan Corporation and Biogen Idec announced that marketing of the monoclonal antibody, which had received U.S. Food and Drug Administration approval months earlier for relapsing forms of multiple sclerosis (MS), was being suspended because of one confirmed case of progressive multifocal leukoencephalopathy (PML) in a patient who had died and a second suspected case.

In early March, the companies announced that this second case had also been confirmed. The patient was a woman who, like the first patient, had been on the drug for over 2 years in combination with interferon beta-1a (Avonex), another Biogen product that was approved for MS in 1996.

One patient had been treated for 38 months, the other, 27 months. No cases of PML, a rare, usually fatal, progressive demyelinating central nervous system disease, have been reported in patients with MS who have used natalizumab as monotherapy, or in the Crohn's disease or rheumatoid arthritis trials. In addition, no cases of PML have been reported in patients who have been treated with interferon beta-1a monotherapy since its approval in 1996.

In March, the FDA suspended clinical trials of all MS drugs that are in the same class as natalizumab, as a precaution. One drug affected is 683699, an investigational agent developed by European drugmaker GlaxoSmithKline, which was in phase II trials at the time of the FDA action.

Since approval in late November, about 5,000 people have been treated with natalizumab, but most had received only a few doses since it is administered intravenously once every 4 weeks. About 3,000 patients had received natalizumab in clinical trials, largely for MS. The drug was also stopped in patients enrolled in smaller trials of rheumatoid arthritis and Crohn's disease.

In the companies' efforts to determine the association between natalizumab and PML, and to determine whether MS patients who may be at risk for developing PML can be identified, the two companies are working with a panel of PML experts, and are reviewing clinical information and MRI scans of all patients in clinical trials. These patients will also undergo physical exams, and will undergo MRIs to look for early signs of PML.

The companies hope to find “a path back for this drug,” Al Sandrock, M.D., vice president of medical research at Biogen Idec, said during a Webcast sponsored by the National MS Society in New York City after the suspension. He would not speculate on when or if it would become available again, but added that the companies recognize the benefits of the drug. Within days of learning about the two cases, the companies decided to suspend marketing, “to step back and assess the risk.”

In a “dear health care professional” letter, the companies advised physicians to evaluate their patients who have taken natalizumab for signs of PML, and to report any suspected cases. Impaired cognition, cortical blindness, and hemiparesis are usually among the presenting symptoms, and characteristic lesions are usually present on MRI scans.

PML primarily affects those who are immunocompromised, with the vast majority of cases today seen in patients with AIDs or HIV. It is caused by the activation of a human polyomavirus, JC virus, which is latent in more than 80% of healthy adults, and can be similar in presentation to MS although the cause of demyelination differs.

The FDA approved natalizumab for reducing the frequency of exacerbations in people with relapsing forms of MS. The accelerated approval was based on the first year of efficacy and safety data from two ongoing international trials of over 2,000 patients, under the condition that the companies complete the second year of the trials.

During the first year of treatment, those on monotherapy had 66% fewer relapses than those on placebo, and in the second trial, those on the combination had 54% fewer relapses than those on interferon beta-1a alone. No major safety concerns were raised in these studies.

During the National MS Society Webcast, Aaron Miller, M.D., said that although PML and MS are both demyelinating diseases, the mechanisms of demyelination are different and PML is “not at all related to MS,” he said. With PML, the virus destroys oligodendrocytes in the brain, which make myelin; but in most if not all cases of MS, an inflammatory process destroys myelin, said Dr. Miller, chief medical officer of the society and medical director of the Corinne Goldsmith Dickinson Center for MS, at Mt. Sinai Medical Center, New York.

Dr. Miller described the PML cases and subsequent suspension of the drug from marketing as “a great tragedy for the entire MS community. We certainly hope that after the dust has cleared, we will be able to find a way to safely bring this drug back to patients,” he said, but added, “that remains to be seen.”

The FDA's public health advisory regarding natalizumabcan be found at www.fda.gov/cder/drug/advisory/natalizumab.htmwww.elan.com

Prospects for the eventual return of the multiple sclerosis treatment natalizumab (Tysabri) became more uncertain when a second case of progressive multifocal leukoencephalopathy was confirmed in a patient who had been treated with the drug for more than 2 years, in combination with interferon beta-1a.

On Feb. 28, Elan Corporation and Biogen Idec announced that marketing of the monoclonal antibody, which had received U.S. Food and Drug Administration approval months earlier for relapsing forms of multiple sclerosis (MS), was being suspended because of one confirmed case of progressive multifocal leukoencephalopathy (PML) in a patient who had died and a second suspected case.

In early March, the companies announced that this second case had also been confirmed. The patient was a woman who, like the first patient, had been on the drug for over 2 years in combination with interferon beta-1a (Avonex), another Biogen product that was approved for MS in 1996.

One patient had been treated for 38 months, the other, 27 months. No cases of PML, a rare, usually fatal, progressive demyelinating central nervous system disease, have been reported in patients with MS who have used natalizumab as monotherapy, or in the Crohn's disease or rheumatoid arthritis trials. In addition, no cases of PML have been reported in patients who have been treated with interferon beta-1a monotherapy since its approval in 1996.

In March, the FDA suspended clinical trials of all MS drugs that are in the same class as natalizumab, as a precaution. One drug affected is 683699, an investigational agent developed by European drugmaker GlaxoSmithKline, which was in phase II trials at the time of the FDA action.

Since approval in late November, about 5,000 people have been treated with natalizumab, but most had received only a few doses since it is administered intravenously once every 4 weeks. About 3,000 patients had received natalizumab in clinical trials, largely for MS. The drug was also stopped in patients enrolled in smaller trials of rheumatoid arthritis and Crohn's disease.

In the companies' efforts to determine the association between natalizumab and PML, and to determine whether MS patients who may be at risk for developing PML can be identified, the two companies are working with a panel of PML experts, and are reviewing clinical information and MRI scans of all patients in clinical trials. These patients will also undergo physical exams, and will undergo MRIs to look for early signs of PML.

The companies hope to find “a path back for this drug,” Al Sandrock, M.D., vice president of medical research at Biogen Idec, said during a Webcast sponsored by the National MS Society in New York City after the suspension. He would not speculate on when or if it would become available again, but added that the companies recognize the benefits of the drug. Within days of learning about the two cases, the companies decided to suspend marketing, “to step back and assess the risk.”

In a “dear health care professional” letter, the companies advised physicians to evaluate their patients who have taken natalizumab for signs of PML, and to report any suspected cases. Impaired cognition, cortical blindness, and hemiparesis are usually among the presenting symptoms, and characteristic lesions are usually present on MRI scans.

PML primarily affects those who are immunocompromised, with the vast majority of cases today seen in patients with AIDs or HIV. It is caused by the activation of a human polyomavirus, JC virus, which is latent in more than 80% of healthy adults, and can be similar in presentation to MS although the cause of demyelination differs.

The FDA approved natalizumab for reducing the frequency of exacerbations in people with relapsing forms of MS. The accelerated approval was based on the first year of efficacy and safety data from two ongoing international trials of over 2,000 patients, under the condition that the companies complete the second year of the trials.

During the first year of treatment, those on monotherapy had 66% fewer relapses than those on placebo, and in the second trial, those on the combination had 54% fewer relapses than those on interferon beta-1a alone. No major safety concerns were raised in these studies.

During the National MS Society Webcast, Aaron Miller, M.D., said that although PML and MS are both demyelinating diseases, the mechanisms of demyelination are different and PML is “not at all related to MS,” he said. With PML, the virus destroys oligodendrocytes in the brain, which make myelin; but in most if not all cases of MS, an inflammatory process destroys myelin, said Dr. Miller, chief medical officer of the society and medical director of the Corinne Goldsmith Dickinson Center for MS, at Mt. Sinai Medical Center, New York.

Dr. Miller described the PML cases and subsequent suspension of the drug from marketing as “a great tragedy for the entire MS community. We certainly hope that after the dust has cleared, we will be able to find a way to safely bring this drug back to patients,” he said, but added, “that remains to be seen.”

The FDA's public health advisory regarding natalizumabcan be found at www.fda.gov/cder/drug/advisory/natalizumab.htmwww.elan.com

International reports of withdrawal symptoms in 93 newborns whose mothers had taken selective serotonin reuptake inhibitors during pregnancy raise concerns about a possible causal relationship between such symptoms and drugs in this class, particularly paroxetine, according to authors of a study that identified these cases.

Nearly two-thirds (64) of these cases were seen in babies whose mothers had taken paroxetine (Paxil), which the authors concluded should not be used in pregnancy, “or, if used, should be given at the lowest effective dose.”

The use of other SSRIs “should be carefully monitored and new cases promptly communicated to the pharmacovigilance systems,” wrote Emilio Sanz, M.D., professor of clinical pharmacology at the University of La Laguna (Spain), and associates (Lancet 2005;365:482–7).

When asked to comment on the study, two experts on drug therapy during pregnancy disagreed with the authors' conclusions, which they said fail to balance the risks and benefits of these drugs in pregnant women with depression.

Gideon Koren, M.D., director of the Motherisk Program, a teratogen information service at the Hospital for Sick Children, Toronto, said that while the identification of these cases in an international database was commendable, he took issue with the conclusion that paroxetine should not be used in pregnancy. This recommendation is not based on an appropriate risk-benefit analysis, he said, and it does not take into account the increased risk of maternal morbidity associated with untreated maternal depression, which is the strongest predictor of postpartum depression.

Moreover, the authors fail to take into account a study published last year, which found that in a large Swedish database, the association between paroxetine and these symptoms was no greater than with other SSRIs, added Dr. Koren, who said he has no financial ties to manufacturers of antidepressants.

He noted that neonatal withdrawal symptoms are self-limited and that the syndrome has “a very benign course,” which also was not discussed by the authors. He and his associates at Motherisk have conducted many prospective case-control studies on the effects of different drugs in pregnancy. One of the studies, published in 2002, found a significantly higher rate of neonatal withdrawal symptoms in newborns exposed to paroxetine in the third trimester, compared with unexposed controls.

Lee Cohen, M.D., director of the perinatal psychiatry program at Massachusetts General Hospital, Boston, emphasized that while an appropriate level of vigilance is warranted in neonates who have been exposed to SSRIs in the third trimester, the cases in the study represent spontaneous reports, not controlled data.

They are “not a clap of thunder” but represent another data set that is starting to suggest that there is some association between SSRI exposure and risk for perinatal syndrome, Dr. Cohen said in an interview.

What complicates the situation is that use of these drugs in the general population and in pregnant women is significant, but the incidence of these symptoms is probably extremely small. There are no controlled data available that can be used to reliably estimate the prevalence of these symptoms in pregnant women on antidepressants, added Dr. Cohen, who is a consultant to manufacturers of several antidepressants.

What concerns him most, Dr. Cohen said, is that the study could not only lead to a reduction in antidepressant use during the peripartum period, but could affect a woman's willingness to take medication she may need at other points during pregnancy. The study also could affect the clinicians' willingness to prescribe therapy when needed during pregnancy.

The study, published last month, involved a search for reports of cases in the WHO adverse drug reaction database, where spontaneous reports of suspected adverse drug reactions are sent from centers in 81 countries. The first case, which was associated with fluoxetine, was reported in 1995. As of November 2003, 93 suspected cases of SSRI-associated neonatal withdrawal syndrome had been reported. In 73 of those cases, no concomitant medications were reported or the concomitant medications were thought to be unrelated to the symptoms.

For 10 of the remaining 20 cases, an association with the SSRIs was considered “doubtful,” because of the concomitant use of medications that included antipsychotics or other drugs for which an association with neonatal withdrawal symptoms have not been clearly established. Another 10 were considered as “probably not” associated with SSRIs, because concomitant medications included drugs like opioids or tricyclics, according to the authors.

The most common neurological symptoms reported were nervousness, abnormal crying, tremors, and hypertonia. Other symptoms included digestive symptoms (vomiting, feeding disorders, or diarrhea), and respiratory symptoms (including two cases of respiratory depression). There were 13 cases of neonatal convulsions–11 listed as neonatal convulsions and 2 as grand mal convulsions.

Of the 93 cases, 64 were associated with exposure to paroxetine, followed by 14 associated with fluoxetine (Prozac), 9 with sertraline (Zoloft), and 7 with citalopram (Celexa). Information on doses and duration of treatment during pregnancy were reported in a minority of cases.

The pharmacokinetic differences between SSRIs “could partly explain their different withdrawal effects,” they said.

For about a decade, there have been reports of withdrawal symptoms in newborns exposed in the third trimester to SSRIs. Symptoms have included irritability, abnormal crying, and difficulty feeding.

Acknowledging these reports, the Food and Drug Administration last year required manufacturers to add information to the labels of SSRIs and selective norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, on clinical findings in newborns exposed to these drugs late in the third trimester, including respiratory distress, jitteriness, irritability, hypoglycemia, feeding difficulties, and constant crying.

A spokesperson for Paxil manufacturer GlaxoSmithKline said the company had no statement on the Lancet report but pointed out that the FDA required this label change for all SSRIs and SNRIs.

International reports of withdrawal symptoms in 93 newborns whose mothers had taken selective serotonin reuptake inhibitors during pregnancy raise concerns about a possible causal relationship between such symptoms and drugs in this class, particularly paroxetine, according to authors of a study that identified these cases.

Nearly two-thirds (64) of these cases were seen in babies whose mothers had taken paroxetine (Paxil), which the authors concluded should not be used in pregnancy, “or, if used, should be given at the lowest effective dose.”

The use of other SSRIs “should be carefully monitored and new cases promptly communicated to the pharmacovigilance systems,” wrote Emilio Sanz, M.D., professor of clinical pharmacology at the University of La Laguna (Spain), and associates (Lancet 2005;365:482–7).

When asked to comment on the study, two experts on drug therapy during pregnancy disagreed with the authors' conclusions, which they said fail to balance the risks and benefits of these drugs in pregnant women with depression.

Gideon Koren, M.D., director of the Motherisk Program, a teratogen information service at the Hospital for Sick Children, Toronto, said that while the identification of these cases in an international database was commendable, he took issue with the conclusion that paroxetine should not be used in pregnancy. This recommendation is not based on an appropriate risk-benefit analysis, he said, and it does not take into account the increased risk of maternal morbidity associated with untreated maternal depression, which is the strongest predictor of postpartum depression.

Moreover, the authors fail to take into account a study published last year, which found that in a large Swedish database, the association between paroxetine and these symptoms was no greater than with other SSRIs, added Dr. Koren, who said he has no financial ties to manufacturers of antidepressants.

He noted that neonatal withdrawal symptoms are self-limited and that the syndrome has “a very benign course,” which also was not discussed by the authors. He and his associates at Motherisk have conducted many prospective case-control studies on the effects of different drugs in pregnancy. One of the studies, published in 2002, found a significantly higher rate of neonatal withdrawal symptoms in newborns exposed to paroxetine in the third trimester, compared with unexposed controls.

Lee Cohen, M.D., director of the perinatal psychiatry program at Massachusetts General Hospital, Boston, emphasized that while an appropriate level of vigilance is warranted in neonates who have been exposed to SSRIs in the third trimester, the cases in the study represent spontaneous reports, not controlled data.

They are “not a clap of thunder” but represent another data set that is starting to suggest that there is some association between SSRI exposure and risk for perinatal syndrome, Dr. Cohen said in an interview.

What complicates the situation is that use of these drugs in the general population and in pregnant women is significant, but the incidence of these symptoms is probably extremely small. There are no controlled data available that can be used to reliably estimate the prevalence of these symptoms in pregnant women on antidepressants, added Dr. Cohen, who is a consultant to manufacturers of several antidepressants.

What concerns him most, Dr. Cohen said, is that the study could not only lead to a reduction in antidepressant use during the peripartum period, but could affect a woman's willingness to take medication she may need at other points during pregnancy. The study also could affect the clinicians' willingness to prescribe therapy when needed during pregnancy.

The study, published last month, involved a search for reports of cases in the WHO adverse drug reaction database, where spontaneous reports of suspected adverse drug reactions are sent from centers in 81 countries. The first case, which was associated with fluoxetine, was reported in 1995. As of November 2003, 93 suspected cases of SSRI-associated neonatal withdrawal syndrome had been reported. In 73 of those cases, no concomitant medications were reported or the concomitant medications were thought to be unrelated to the symptoms.

For 10 of the remaining 20 cases, an association with the SSRIs was considered “doubtful,” because of the concomitant use of medications that included antipsychotics or other drugs for which an association with neonatal withdrawal symptoms have not been clearly established. Another 10 were considered as “probably not” associated with SSRIs, because concomitant medications included drugs like opioids or tricyclics, according to the authors.

The most common neurological symptoms reported were nervousness, abnormal crying, tremors, and hypertonia. Other symptoms included digestive symptoms (vomiting, feeding disorders, or diarrhea), and respiratory symptoms (including two cases of respiratory depression). There were 13 cases of neonatal convulsions–11 listed as neonatal convulsions and 2 as grand mal convulsions.

Of the 93 cases, 64 were associated with exposure to paroxetine, followed by 14 associated with fluoxetine (Prozac), 9 with sertraline (Zoloft), and 7 with citalopram (Celexa). Information on doses and duration of treatment during pregnancy were reported in a minority of cases.

The pharmacokinetic differences between SSRIs “could partly explain their different withdrawal effects,” they said.

For about a decade, there have been reports of withdrawal symptoms in newborns exposed in the third trimester to SSRIs. Symptoms have included irritability, abnormal crying, and difficulty feeding.

Acknowledging these reports, the Food and Drug Administration last year required manufacturers to add information to the labels of SSRIs and selective norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, on clinical findings in newborns exposed to these drugs late in the third trimester, including respiratory distress, jitteriness, irritability, hypoglycemia, feeding difficulties, and constant crying.

A spokesperson for Paxil manufacturer GlaxoSmithKline said the company had no statement on the Lancet report but pointed out that the FDA required this label change for all SSRIs and SNRIs.

International reports of withdrawal symptoms in 93 newborns whose mothers had taken selective serotonin reuptake inhibitors during pregnancy raise concerns about a possible causal relationship between such symptoms and drugs in this class, particularly paroxetine, according to authors of a study that identified these cases.

Nearly two-thirds (64) of these cases were seen in babies whose mothers had taken paroxetine (Paxil), which the authors concluded should not be used in pregnancy, “or, if used, should be given at the lowest effective dose.”

The use of other SSRIs “should be carefully monitored and new cases promptly communicated to the pharmacovigilance systems,” wrote Emilio Sanz, M.D., professor of clinical pharmacology at the University of La Laguna (Spain), and associates (Lancet 2005;365:482–7).

When asked to comment on the study, two experts on drug therapy during pregnancy disagreed with the authors' conclusions, which they said fail to balance the risks and benefits of these drugs in pregnant women with depression.

Gideon Koren, M.D., director of the Motherisk Program, a teratogen information service at the Hospital for Sick Children, Toronto, said that while the identification of these cases in an international database was commendable, he took issue with the conclusion that paroxetine should not be used in pregnancy. This recommendation is not based on an appropriate risk-benefit analysis, he said, and it does not take into account the increased risk of maternal morbidity associated with untreated maternal depression, which is the strongest predictor of postpartum depression.

Moreover, the authors fail to take into account a study published last year, which found that in a large Swedish database, the association between paroxetine and these symptoms was no greater than with other SSRIs, added Dr. Koren, who said he has no financial ties to manufacturers of antidepressants.

He noted that neonatal withdrawal symptoms are self-limited and that the syndrome has “a very benign course,” which also was not discussed by the authors. He and his associates at Motherisk have conducted many prospective case-control studies on the effects of different drugs in pregnancy. One of the studies, published in 2002, found a significantly higher rate of neonatal withdrawal symptoms in newborns exposed to paroxetine in the third trimester, compared with unexposed controls.

Lee Cohen, M.D., director of the perinatal psychiatry program at Massachusetts General Hospital, Boston, emphasized that while an appropriate level of vigilance is warranted in neonates who have been exposed to SSRIs in the third trimester, the cases in the study represent spontaneous reports, not controlled data.

They are “not a clap of thunder” but represent another data set that is starting to suggest that there is some association between SSRI exposure and risk for perinatal syndrome, Dr. Cohen said in an interview.

What complicates the situation is that use of these drugs in the general population and in pregnant women is significant, but the incidence of these symptoms is probably extremely small. There are no controlled data available that can be used to reliably estimate the prevalence of these symptoms in pregnant women on antidepressants, added Dr. Cohen, who is a consultant to manufacturers of several antidepressants.

What concerns him most, Dr. Cohen said, is that the study could not only lead to a reduction in antidepressant use during the peripartum period, but could affect a woman's willingness to take medication she may need at other points during pregnancy. The study also could affect the clinicians' willingness to prescribe therapy when needed during pregnancy.

The study, published last month, involved a search for reports of cases in the WHO adverse drug reaction database, where spontaneous reports of suspected adverse drug reactions are sent from centers in 81 countries. The first case, which was associated with fluoxetine, was reported in 1995. As of November 2003, 93 suspected cases of SSRI-associated neonatal withdrawal syndrome had been reported. In 73 of those cases, no concomitant medications were reported or the concomitant medications were thought to be unrelated to the symptoms.

For 10 of the remaining 20 cases, an association with the SSRIs was considered “doubtful,” because of the concomitant use of medications that included antipsychotics or other drugs for which an association with neonatal withdrawal symptoms have not been clearly established. Another 10 were considered as “probably not” associated with SSRIs, because concomitant medications included drugs like opioids or tricyclics, according to the authors.

The most common neurological symptoms reported were nervousness, abnormal crying, tremors, and hypertonia. Other symptoms included digestive symptoms (vomiting, feeding disorders, or diarrhea), and respiratory symptoms (including two cases of respiratory depression). There were 13 cases of neonatal convulsions–11 listed as neonatal convulsions and 2 as grand mal convulsions.

Of the 93 cases, 64 were associated with exposure to paroxetine, followed by 14 associated with fluoxetine (Prozac), 9 with sertraline (Zoloft), and 7 with citalopram (Celexa). Information on doses and duration of treatment during pregnancy were reported in a minority of cases.

The pharmacokinetic differences between SSRIs “could partly explain their different withdrawal effects,” they said.

For about a decade, there have been reports of withdrawal symptoms in newborns exposed in the third trimester to SSRIs. Symptoms have included irritability, abnormal crying, and difficulty feeding.

Acknowledging these reports, the Food and Drug Administration last year required manufacturers to add information to the labels of SSRIs and selective norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, on clinical findings in newborns exposed to these drugs late in the third trimester, including respiratory distress, jitteriness, irritability, hypoglycemia, feeding difficulties, and constant crying.

A spokesperson for Paxil manufacturer GlaxoSmithKline said the company had no statement on the Lancet report but pointed out that the FDA required this label change for all SSRIs and SNRIs.

GAITHERSBURG, MD. — A Food and Drug Administration panel in a 9–2 vote recommended against approval of a spectroscopy-based cervical imaging device designed to be used as an adjunct to colposcopy in women with ASCUS/LSIL Pap smears, citing weaknesses in clinical trial data for effectiveness and other concerns.

At a meeting last month, the FDA's Obstetrics and Gynecology Devices Panel reviewed the results of the two pivotal trials of the device, the LUMA Cervical Imaging System, manufactured by Massachusetts-based MediSpectra Inc.

The indication under FDA review is for use as an adjunct to colposcopy for identifying high-grade disease (cervical intraepithelial neoplasia-CIN 2/3/) in women who have an ASCUS or LSIL cervical cytology result and are referred for colposcopy.

This proposed indication is accompanied by the statement that the device is not intended to replace colposcopy and that “a thorough colposcopic evaluation with an identification or selection of biopsy sites must be performed independently and prior to the viewing of the LUMA results.”

The LUMA device is a stand-alone, mobile optical analysis system, with components that include a console that contains an ultraviolet laser, an illumination probe, and a computer. The system uses ultraviolet and visible light to illuminate the cervix, producing an image with areas highlighted in blue that may not have been seen on colposcopy and that can then be biopsied. The scan is obtained, and the colposcopic exam and biopsies are performed. Then the LUMA scan is displayed on the device console.

The two studies enrolled 2,526 patients aged 18 years and older who were seen at 13 institutions. The women had abnormal Pap smear results: atypical cells of undetermined significance (ASCUS), low-grade squamous lesions (LSIL), high-grade squamous lesions (HSIL), or cancer. Colposcopies were performed by 52 expert colposcopists. The primary effectiveness end points were the true positive (patients with at least one biopsy diagnostic of CIN 2/3/) and false-positive rates.

In the first study, the true positive rate was only 1.9% greater among those who had colposcopy with the LUMA scan than among those who had only a colposcopy—a statistically insignificant difference.

The false-positive rate was 3.1% higher among those having both procedures, which was considered clinically acceptable (defined as a false-positive rate that was not more than 8% greater than that of colposcopy alone).

Among women with ASCUS/LSIL results, the true positive rate was 3% higher with the addition of LUMA, which was statistically insignificant.

In the second study of 227 women, the LUMA scan was done but not revealed to the colposcopist until after the colposcopy was completed; biopsies were then taken based on the LUMA scan results. With the LUMA scan, the overall true positive rate increased by 4.7%, which was significant, but the false-positive rate increased by 18%, which did not meet the prehypothesis that the false-positive rate would not exceed 15%.

When only ASCUS/LSIL patients were analyzed, neither the true nor the false-positive rate end point was met.

In voting against approval, Hugh Miller, M.D., of the Arizona Health Science Center, Tucson, said that he was not convinced that the device “would provide a significant benefit over and above a skilled colposcopist doing an adequate number of biopsies.”

He described it as “a technology in motion,” which had certain risks that included over- and underdiagnosis, as well as “potentially a dumbing down of a skill set,” that needs to be improved. He and others raised the concern that over time, colposcopists might lean more on LUMA for directing their biopsies and rely less on colposcopy, which is more effective.

Other panelists voting against approval cited concerns that included the potential regression of CIN 2 lesions in younger patients without treatment, and that the benefit appeared to be mostly in younger patients.

After the panel vote, MediSpectra officials had no comment regarding their plans. The FDA usually follows the recommendations of its advisory panels.

GAITHERSBURG, MD. — A Food and Drug Administration panel in a 9–2 vote recommended against approval of a spectroscopy-based cervical imaging device designed to be used as an adjunct to colposcopy in women with ASCUS/LSIL Pap smears, citing weaknesses in clinical trial data for effectiveness and other concerns.

At a meeting last month, the FDA's Obstetrics and Gynecology Devices Panel reviewed the results of the two pivotal trials of the device, the LUMA Cervical Imaging System, manufactured by Massachusetts-based MediSpectra Inc.

The indication under FDA review is for use as an adjunct to colposcopy for identifying high-grade disease (cervical intraepithelial neoplasia-CIN 2/3/) in women who have an ASCUS or LSIL cervical cytology result and are referred for colposcopy.

This proposed indication is accompanied by the statement that the device is not intended to replace colposcopy and that “a thorough colposcopic evaluation with an identification or selection of biopsy sites must be performed independently and prior to the viewing of the LUMA results.”

The LUMA device is a stand-alone, mobile optical analysis system, with components that include a console that contains an ultraviolet laser, an illumination probe, and a computer. The system uses ultraviolet and visible light to illuminate the cervix, producing an image with areas highlighted in blue that may not have been seen on colposcopy and that can then be biopsied. The scan is obtained, and the colposcopic exam and biopsies are performed. Then the LUMA scan is displayed on the device console.

The two studies enrolled 2,526 patients aged 18 years and older who were seen at 13 institutions. The women had abnormal Pap smear results: atypical cells of undetermined significance (ASCUS), low-grade squamous lesions (LSIL), high-grade squamous lesions (HSIL), or cancer. Colposcopies were performed by 52 expert colposcopists. The primary effectiveness end points were the true positive (patients with at least one biopsy diagnostic of CIN 2/3/) and false-positive rates.

In the first study, the true positive rate was only 1.9% greater among those who had colposcopy with the LUMA scan than among those who had only a colposcopy—a statistically insignificant difference.

The false-positive rate was 3.1% higher among those having both procedures, which was considered clinically acceptable (defined as a false-positive rate that was not more than 8% greater than that of colposcopy alone).

Among women with ASCUS/LSIL results, the true positive rate was 3% higher with the addition of LUMA, which was statistically insignificant.

In the second study of 227 women, the LUMA scan was done but not revealed to the colposcopist until after the colposcopy was completed; biopsies were then taken based on the LUMA scan results. With the LUMA scan, the overall true positive rate increased by 4.7%, which was significant, but the false-positive rate increased by 18%, which did not meet the prehypothesis that the false-positive rate would not exceed 15%.

When only ASCUS/LSIL patients were analyzed, neither the true nor the false-positive rate end point was met.

In voting against approval, Hugh Miller, M.D., of the Arizona Health Science Center, Tucson, said that he was not convinced that the device “would provide a significant benefit over and above a skilled colposcopist doing an adequate number of biopsies.”

He described it as “a technology in motion,” which had certain risks that included over- and underdiagnosis, as well as “potentially a dumbing down of a skill set,” that needs to be improved. He and others raised the concern that over time, colposcopists might lean more on LUMA for directing their biopsies and rely less on colposcopy, which is more effective.

Other panelists voting against approval cited concerns that included the potential regression of CIN 2 lesions in younger patients without treatment, and that the benefit appeared to be mostly in younger patients.

After the panel vote, MediSpectra officials had no comment regarding their plans. The FDA usually follows the recommendations of its advisory panels.

GAITHERSBURG, MD. — A Food and Drug Administration panel in a 9–2 vote recommended against approval of a spectroscopy-based cervical imaging device designed to be used as an adjunct to colposcopy in women with ASCUS/LSIL Pap smears, citing weaknesses in clinical trial data for effectiveness and other concerns.

At a meeting last month, the FDA's Obstetrics and Gynecology Devices Panel reviewed the results of the two pivotal trials of the device, the LUMA Cervical Imaging System, manufactured by Massachusetts-based MediSpectra Inc.

The indication under FDA review is for use as an adjunct to colposcopy for identifying high-grade disease (cervical intraepithelial neoplasia-CIN 2/3/) in women who have an ASCUS or LSIL cervical cytology result and are referred for colposcopy.

This proposed indication is accompanied by the statement that the device is not intended to replace colposcopy and that “a thorough colposcopic evaluation with an identification or selection of biopsy sites must be performed independently and prior to the viewing of the LUMA results.”

The LUMA device is a stand-alone, mobile optical analysis system, with components that include a console that contains an ultraviolet laser, an illumination probe, and a computer. The system uses ultraviolet and visible light to illuminate the cervix, producing an image with areas highlighted in blue that may not have been seen on colposcopy and that can then be biopsied. The scan is obtained, and the colposcopic exam and biopsies are performed. Then the LUMA scan is displayed on the device console.

The two studies enrolled 2,526 patients aged 18 years and older who were seen at 13 institutions. The women had abnormal Pap smear results: atypical cells of undetermined significance (ASCUS), low-grade squamous lesions (LSIL), high-grade squamous lesions (HSIL), or cancer. Colposcopies were performed by 52 expert colposcopists. The primary effectiveness end points were the true positive (patients with at least one biopsy diagnostic of CIN 2/3/) and false-positive rates.

In the first study, the true positive rate was only 1.9% greater among those who had colposcopy with the LUMA scan than among those who had only a colposcopy—a statistically insignificant difference.

The false-positive rate was 3.1% higher among those having both procedures, which was considered clinically acceptable (defined as a false-positive rate that was not more than 8% greater than that of colposcopy alone).

Among women with ASCUS/LSIL results, the true positive rate was 3% higher with the addition of LUMA, which was statistically insignificant.

In the second study of 227 women, the LUMA scan was done but not revealed to the colposcopist until after the colposcopy was completed; biopsies were then taken based on the LUMA scan results. With the LUMA scan, the overall true positive rate increased by 4.7%, which was significant, but the false-positive rate increased by 18%, which did not meet the prehypothesis that the false-positive rate would not exceed 15%.

When only ASCUS/LSIL patients were analyzed, neither the true nor the false-positive rate end point was met.

In voting against approval, Hugh Miller, M.D., of the Arizona Health Science Center, Tucson, said that he was not convinced that the device “would provide a significant benefit over and above a skilled colposcopist doing an adequate number of biopsies.”

He described it as “a technology in motion,” which had certain risks that included over- and underdiagnosis, as well as “potentially a dumbing down of a skill set,” that needs to be improved. He and others raised the concern that over time, colposcopists might lean more on LUMA for directing their biopsies and rely less on colposcopy, which is more effective.

Other panelists voting against approval cited concerns that included the potential regression of CIN 2 lesions in younger patients without treatment, and that the benefit appeared to be mostly in younger patients.

After the panel vote, MediSpectra officials had no comment regarding their plans. The FDA usually follows the recommendations of its advisory panels.

A once-monthly formulation of the bisphosphonate ibandronate was recently approved by the Food and Drug Administration for treating postmenopausal osteoporosis, 2 years after a daily formulation of the drug was approved but never marketed.

Ibandronate, which is being marketed as Boniva by Roche, is the third oral bisphosphonate and the first monthly formulation marketed in the United States for osteoporosis. It was approved in late March.

A 2.5-mg daily formulation was approved in 2003, based on a 3-year study that showed a reduction in vertebral fracture risk, but it was never marketed because of the availability of the more convenient, weekly bisphosphonate formulations, alendronate (Fosamax) and risedronate (Actonel).

Approval of the once-monthly 150-mg formulation of ibandronate was based on a 1-year noninferiority study of 1,602 postmenopausal women. The study showed that bone mineral density (BMD) increases in the lumbar spine in patients on monthly ibandronate were significantly higher than in those on 2.5 mg of ibandronate daily (4.85% vs. 3.86%). BMD increases at other skeletal sites also were “consistently higher” among those on the monthly dose, according to the drug's label.

Approval of the daily formulation was based on a 3-year study of almost 3,000 women with postmenopausal osteoporosis; the risk of having a vertebral fracture was 4.7% among those on ibandronate, vs. 9.6% among those on placebo, a highly significant difference.

Over the past decade, several new choices for osteoporosis treatment and prevention have become available, each a little different from the others, providing more opportunities to individualize therapy, said Ethel Siris, M.D., director of the Toni Stabile Osteoporosis Center at New York-Presbyterian Hospital and the Madeline C. Stabile professor of clinical medicine, Columbia University, New York.

The fracture data in the trials of these three drugs are somewhat different, she observed, noting that in the initial 3-year study, daily ibandronate was found to reduce the vertebral fracture risk “quite substantially” but did not reduce the risk of nonvertebral fractures. Alendronate, on the other hand, has been shown to reduce vertebral and hip fractures, and risedronate has been shown to reduce vertebral and nonvertebral fractures, reflected in approved indications, she added in an interview.

In a subgroup of patients with very low T scores in the initial ibandronate study, there was a reduction in nonvertebral fracture risk among those on 2.5 mg, compared with placebo, but that was a post hoc analysis and not a prespecified end point, she said.

Another difference between ibandronate and the other two oral bisphosphonates is that a patient needs to sit or stand for 1 hour after taking ibandronate, compared with only 1/2 hour for the other two agents, she said.

Dr. Siris, a consultant to the manufacturers of alendronate and risedronate, has served on an advisory board for GlaxoSmithKline, which is copromoting ibandronate with Roche.

The recommended dosage of monthly ibandronate is one 150-mg tablet taken on the same day once a month, swallowed with a 6- to 8-ounce glass of water, while standing or sitting. The patient should then wait 60 minutes before lying down or eating, drinking, or taking other medications (to reduce the risk of esophageal irritation). Esophagitis, the main side effect of bisphosphonates, is reduced with less frequent dosing but can still occur.

A once-monthly formulation of the bisphosphonate ibandronate was recently approved by the Food and Drug Administration for treating postmenopausal osteoporosis, 2 years after a daily formulation of the drug was approved but never marketed.

Ibandronate, which is being marketed as Boniva by Roche, is the third oral bisphosphonate and the first monthly formulation marketed in the United States for osteoporosis. It was approved in late March.

A 2.5-mg daily formulation was approved in 2003, based on a 3-year study that showed a reduction in vertebral fracture risk, but it was never marketed because of the availability of the more convenient, weekly bisphosphonate formulations, alendronate (Fosamax) and risedronate (Actonel).

Approval of the once-monthly 150-mg formulation of ibandronate was based on a 1-year noninferiority study of 1,602 postmenopausal women. The study showed that bone mineral density (BMD) increases in the lumbar spine in patients on monthly ibandronate were significantly higher than in those on 2.5 mg of ibandronate daily (4.85% vs. 3.86%). BMD increases at other skeletal sites also were “consistently higher” among those on the monthly dose, according to the drug's label.

Approval of the daily formulation was based on a 3-year study of almost 3,000 women with postmenopausal osteoporosis; the risk of having a vertebral fracture was 4.7% among those on ibandronate, vs. 9.6% among those on placebo, a highly significant difference.

Over the past decade, several new choices for osteoporosis treatment and prevention have become available, each a little different from the others, providing more opportunities to individualize therapy, said Ethel Siris, M.D., director of the Toni Stabile Osteoporosis Center at New York-Presbyterian Hospital and the Madeline C. Stabile professor of clinical medicine, Columbia University, New York.

The fracture data in the trials of these three drugs are somewhat different, she observed, noting that in the initial 3-year study, daily ibandronate was found to reduce the vertebral fracture risk “quite substantially” but did not reduce the risk of nonvertebral fractures. Alendronate, on the other hand, has been shown to reduce vertebral and hip fractures, and risedronate has been shown to reduce vertebral and nonvertebral fractures, reflected in approved indications, she added in an interview.

In a subgroup of patients with very low T scores in the initial ibandronate study, there was a reduction in nonvertebral fracture risk among those on 2.5 mg, compared with placebo, but that was a post hoc analysis and not a prespecified end point, she said.

Another difference between ibandronate and the other two oral bisphosphonates is that a patient needs to sit or stand for 1 hour after taking ibandronate, compared with only 1/2 hour for the other two agents, she said.

Dr. Siris, a consultant to the manufacturers of alendronate and risedronate, has served on an advisory board for GlaxoSmithKline, which is copromoting ibandronate with Roche.

The recommended dosage of monthly ibandronate is one 150-mg tablet taken on the same day once a month, swallowed with a 6- to 8-ounce glass of water, while standing or sitting. The patient should then wait 60 minutes before lying down or eating, drinking, or taking other medications (to reduce the risk of esophageal irritation). Esophagitis, the main side effect of bisphosphonates, is reduced with less frequent dosing but can still occur.

A once-monthly formulation of the bisphosphonate ibandronate was recently approved by the Food and Drug Administration for treating postmenopausal osteoporosis, 2 years after a daily formulation of the drug was approved but never marketed.

Ibandronate, which is being marketed as Boniva by Roche, is the third oral bisphosphonate and the first monthly formulation marketed in the United States for osteoporosis. It was approved in late March.

A 2.5-mg daily formulation was approved in 2003, based on a 3-year study that showed a reduction in vertebral fracture risk, but it was never marketed because of the availability of the more convenient, weekly bisphosphonate formulations, alendronate (Fosamax) and risedronate (Actonel).

Approval of the once-monthly 150-mg formulation of ibandronate was based on a 1-year noninferiority study of 1,602 postmenopausal women. The study showed that bone mineral density (BMD) increases in the lumbar spine in patients on monthly ibandronate were significantly higher than in those on 2.5 mg of ibandronate daily (4.85% vs. 3.86%). BMD increases at other skeletal sites also were “consistently higher” among those on the monthly dose, according to the drug's label.

Approval of the daily formulation was based on a 3-year study of almost 3,000 women with postmenopausal osteoporosis; the risk of having a vertebral fracture was 4.7% among those on ibandronate, vs. 9.6% among those on placebo, a highly significant difference.

Over the past decade, several new choices for osteoporosis treatment and prevention have become available, each a little different from the others, providing more opportunities to individualize therapy, said Ethel Siris, M.D., director of the Toni Stabile Osteoporosis Center at New York-Presbyterian Hospital and the Madeline C. Stabile professor of clinical medicine, Columbia University, New York.

The fracture data in the trials of these three drugs are somewhat different, she observed, noting that in the initial 3-year study, daily ibandronate was found to reduce the vertebral fracture risk “quite substantially” but did not reduce the risk of nonvertebral fractures. Alendronate, on the other hand, has been shown to reduce vertebral and hip fractures, and risedronate has been shown to reduce vertebral and nonvertebral fractures, reflected in approved indications, she added in an interview.

In a subgroup of patients with very low T scores in the initial ibandronate study, there was a reduction in nonvertebral fracture risk among those on 2.5 mg, compared with placebo, but that was a post hoc analysis and not a prespecified end point, she said.

Another difference between ibandronate and the other two oral bisphosphonates is that a patient needs to sit or stand for 1 hour after taking ibandronate, compared with only 1/2 hour for the other two agents, she said.

Dr. Siris, a consultant to the manufacturers of alendronate and risedronate, has served on an advisory board for GlaxoSmithKline, which is copromoting ibandronate with Roche.

The recommended dosage of monthly ibandronate is one 150-mg tablet taken on the same day once a month, swallowed with a 6- to 8-ounce glass of water, while standing or sitting. The patient should then wait 60 minutes before lying down or eating, drinking, or taking other medications (to reduce the risk of esophageal irritation). Esophagitis, the main side effect of bisphosphonates, is reduced with less frequent dosing but can still occur.

More than a decade after it was taken off the market because of manufacturing issues, the contraceptive sponge has been cleared by the Food and Drug Administration and is expected to be available this summer.

The Today Sponge, which is made of polyurethane foam and contains a 1-g reservoir of nonoxynol-9, will be available over the counter this summer, according to Allendale Pharmaceuticals Inc., the N.J.-based company that bought the rights to the product in 1998. It is the same device taken off the market in 1994, when safety issues were raised with the facilities where the sponge was manufactured.

One sponge, which provides a barrier between the cervix and sperm, continually releases 125ndash;150 mg of nonoxynol-9 into the vagina and can be used for 24 hours, the company said. The polyurethane foam “traps and absorbs semen” before the sperm are able to enter the cervix. It must be left in place for at least 6 hours after the last act of intercourse, and it does not protect against sexually transmitted diseases, the company said.

In multicenter clinical trials of more than 1,800 women conducted in the United States and eight other countries before the device was pulled from the market, the sponge was 89% effective in preventing pregnancies during 1 year among 939 parous women studied and 91% effective among 915 nulliparous women studied, when used properly for every act of intercourse, according to the company. When used improperly and inconsistently, the effectiveness rate ranged from 84%ndash;87%, the company said.

Use of the Today Sponge is contraindicated in individuals who are allergic or sensitive to nonoxynol-9. Typical symptoms can include vaginal burning, itching, redness, rash, and irritation. In the U.S. portion of the clinical study, 4% of women discontinued use of the sponge due to allergic symptoms. Worldwide, this figure was 2.1%. If the user or her partner is allergic to sulfa drugs, he or she should consult a physician before using the sponge.

The sponge is contraindicated for use during menstruation. Some cases of nonmenstrual toxic shock syndrome have been reported in women using barrier contraceptives, including Today Sponge, the diaphragm, and the cervical cap.

More than a decade after it was taken off the market because of manufacturing issues, the contraceptive sponge has been cleared by the Food and Drug Administration and is expected to be available this summer.

The Today Sponge, which is made of polyurethane foam and contains a 1-g reservoir of nonoxynol-9, will be available over the counter this summer, according to Allendale Pharmaceuticals Inc., the N.J.-based company that bought the rights to the product in 1998. It is the same device taken off the market in 1994, when safety issues were raised with the facilities where the sponge was manufactured.

One sponge, which provides a barrier between the cervix and sperm, continually releases 125ndash;150 mg of nonoxynol-9 into the vagina and can be used for 24 hours, the company said. The polyurethane foam “traps and absorbs semen” before the sperm are able to enter the cervix. It must be left in place for at least 6 hours after the last act of intercourse, and it does not protect against sexually transmitted diseases, the company said.

In multicenter clinical trials of more than 1,800 women conducted in the United States and eight other countries before the device was pulled from the market, the sponge was 89% effective in preventing pregnancies during 1 year among 939 parous women studied and 91% effective among 915 nulliparous women studied, when used properly for every act of intercourse, according to the company. When used improperly and inconsistently, the effectiveness rate ranged from 84%ndash;87%, the company said.

Use of the Today Sponge is contraindicated in individuals who are allergic or sensitive to nonoxynol-9. Typical symptoms can include vaginal burning, itching, redness, rash, and irritation. In the U.S. portion of the clinical study, 4% of women discontinued use of the sponge due to allergic symptoms. Worldwide, this figure was 2.1%. If the user or her partner is allergic to sulfa drugs, he or she should consult a physician before using the sponge.

The sponge is contraindicated for use during menstruation. Some cases of nonmenstrual toxic shock syndrome have been reported in women using barrier contraceptives, including Today Sponge, the diaphragm, and the cervical cap.

More than a decade after it was taken off the market because of manufacturing issues, the contraceptive sponge has been cleared by the Food and Drug Administration and is expected to be available this summer.

The Today Sponge, which is made of polyurethane foam and contains a 1-g reservoir of nonoxynol-9, will be available over the counter this summer, according to Allendale Pharmaceuticals Inc., the N.J.-based company that bought the rights to the product in 1998. It is the same device taken off the market in 1994, when safety issues were raised with the facilities where the sponge was manufactured.

One sponge, which provides a barrier between the cervix and sperm, continually releases 125ndash;150 mg of nonoxynol-9 into the vagina and can be used for 24 hours, the company said. The polyurethane foam “traps and absorbs semen” before the sperm are able to enter the cervix. It must be left in place for at least 6 hours after the last act of intercourse, and it does not protect against sexually transmitted diseases, the company said.

In multicenter clinical trials of more than 1,800 women conducted in the United States and eight other countries before the device was pulled from the market, the sponge was 89% effective in preventing pregnancies during 1 year among 939 parous women studied and 91% effective among 915 nulliparous women studied, when used properly for every act of intercourse, according to the company. When used improperly and inconsistently, the effectiveness rate ranged from 84%ndash;87%, the company said.

Use of the Today Sponge is contraindicated in individuals who are allergic or sensitive to nonoxynol-9. Typical symptoms can include vaginal burning, itching, redness, rash, and irritation. In the U.S. portion of the clinical study, 4% of women discontinued use of the sponge due to allergic symptoms. Worldwide, this figure was 2.1%. If the user or her partner is allergic to sulfa drugs, he or she should consult a physician before using the sponge.

The sponge is contraindicated for use during menstruation. Some cases of nonmenstrual toxic shock syndrome have been reported in women using barrier contraceptives, including Today Sponge, the diaphragm, and the cervical cap.

ROCKVILLE, MD. — The angiotensin receptor blocker candesartan should be approved as a treatment for heart failure in patients who are on an ACE inhibitor, a Food and Drug Administration advisory panel has unanimously recommended.

The FDA's cardiovascular and renal drugs advisory committee backed the approval on the basis of results of one of the three Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials.

In CHARM-Added, candesartan (titrated to a target dose of 32 mg/day) was compared with placebo in 2,548 patients with New York Heart Association (NYHA) class II-IV heart failure (HF) and a left ventricular ejection fraction (LVEF) at or below 40% who were on an ACE inhibitor and standard therapy. The results showed that adding an ARB to standard treatment that included an ACE inhibitor added an incremental benefit in this population: The relative risk of cardiovascular mortality or HF hospitalization—the primary end point—was reduced by 15% in those on candesartan during a median follow-up of 41 months. The benefits were also seen in patients treated with β-blockers, which suggested no adverse interactions among β-blockers, candesartan, and ACE inhibitors, as was noted in the Valsartan Heart Failure Trial (Val-HeFT), in which HF morbidity was worse in patients on an ACE inhibitor, β-blocker, and valsartan, according to the FDA.

The purpose of the panel meeting was to determine, according to the FDA's agenda, “whether CHARM-Added provides compelling evidence that candesartan should, under some circumstances, be recommended for use in patients on an ACE inhibitor.”

But a large portion of the meeting was spent discussing whether patients in the trial were on optimal ACE inhibitor doses and whether the same benefits might have been achieved by increasing the dose of the ACE inhibitor.

Although panelists said a forced titration of ACE inhibitor therapy in the study protocol would have been ideal, they said they felt comfortable that the ACE inhibitor doses used fell into the ranges considered adequate or optimal. The “final doses of ACE inhibitor achieved were quite substantial” and in line with the doses seen in other trials of ACE inhibitor therapy, said Blasé Carabello, M.D., professor of medicine at Baylor University, Houston. In addition, an analysis of a subset of patients on high doses of ACE inhibitors “all go in the same direction” favoring the benefit.

The FDA usually follows the recommendations of its advisory panels, which are made up of outside experts. If approved, candesartan (marketed as Atacand by AstraZeneca Pharmaceuticals LP) will be the first ARB approved for use with an ACE inhibitor. Shortly before the panel meeting, the agency approved candesartan for patients with NYHA class II-IV heart failure, and an LVEF at or below 40%, who are not on an ACE inhibitor, to reduce the risk of death from cardiovascular causes and reduce HF hospitalization based on the CHARM-Alternative trial.

Speaking for AstraZeneca at the meeting, John McMurray, M.D., the principal investigator of CHARM-Added, said that 96% of the patients in the trial were taking an “individualized, optimum” dose of an ACE inhibitor at baseline, and about 80% of patients were on one of five ACE inhibitors that were considered preferred because of randomized controlled outcome studies of these drugs, said Dr. McMurray, professor of medical cardiology, Western Infirmary, Glasgow, Scotland.

Speaking on the study's efficacy for AstraZeneca, Marc Pfeffer, M.D., interim chair of medicine at Brigham and Women's Hospital, Boston, and cochair of the CHARM executive committee, said that in CHARM-Added, there was there was no evidence that the beneficial effect of candesartan on cardiovascular death or HF hospitalization, was modified “based on ACE inhibitor dose or choice of ACE inhibitor.”

James Hainer, M.D., senior director of clinical research at AstraZeneca, said that as expected, due to a greater degree of renin-angiotensin-aldosterone system inhibition, rates of hypotension, abnormal renal function, and hyperkalemia were greater with candesartan. However, these adverse events did not translate into any increases in all-cause hospitalization and/or mortality, sudden death, renal failure, or ventricular fibrillation, he said.

These risks will be addressed on the label in warnings and precautions about hypotension, renal dysfunction, and hyperkalemia and recommendations for monitoring and reducing risk, and through interactions with major societies and treatment guidelines committees, he said.

Dr. McMurray said that on balance, the risk was “substantially” in favor of candesartan: A cost analysis found that for every 1,000 patients treated with candesartan, there were 1,900 fewer days spent in the hospital for worsening heart failure, he told the panel.

ROCKVILLE, MD. — The angiotensin receptor blocker candesartan should be approved as a treatment for heart failure in patients who are on an ACE inhibitor, a Food and Drug Administration advisory panel has unanimously recommended.

The FDA's cardiovascular and renal drugs advisory committee backed the approval on the basis of results of one of the three Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials.

In CHARM-Added, candesartan (titrated to a target dose of 32 mg/day) was compared with placebo in 2,548 patients with New York Heart Association (NYHA) class II-IV heart failure (HF) and a left ventricular ejection fraction (LVEF) at or below 40% who were on an ACE inhibitor and standard therapy. The results showed that adding an ARB to standard treatment that included an ACE inhibitor added an incremental benefit in this population: The relative risk of cardiovascular mortality or HF hospitalization—the primary end point—was reduced by 15% in those on candesartan during a median follow-up of 41 months. The benefits were also seen in patients treated with β-blockers, which suggested no adverse interactions among β-blockers, candesartan, and ACE inhibitors, as was noted in the Valsartan Heart Failure Trial (Val-HeFT), in which HF morbidity was worse in patients on an ACE inhibitor, β-blocker, and valsartan, according to the FDA.

The purpose of the panel meeting was to determine, according to the FDA's agenda, “whether CHARM-Added provides compelling evidence that candesartan should, under some circumstances, be recommended for use in patients on an ACE inhibitor.”

But a large portion of the meeting was spent discussing whether patients in the trial were on optimal ACE inhibitor doses and whether the same benefits might have been achieved by increasing the dose of the ACE inhibitor.

Although panelists said a forced titration of ACE inhibitor therapy in the study protocol would have been ideal, they said they felt comfortable that the ACE inhibitor doses used fell into the ranges considered adequate or optimal. The “final doses of ACE inhibitor achieved were quite substantial” and in line with the doses seen in other trials of ACE inhibitor therapy, said Blasé Carabello, M.D., professor of medicine at Baylor University, Houston. In addition, an analysis of a subset of patients on high doses of ACE inhibitors “all go in the same direction” favoring the benefit.

The FDA usually follows the recommendations of its advisory panels, which are made up of outside experts. If approved, candesartan (marketed as Atacand by AstraZeneca Pharmaceuticals LP) will be the first ARB approved for use with an ACE inhibitor. Shortly before the panel meeting, the agency approved candesartan for patients with NYHA class II-IV heart failure, and an LVEF at or below 40%, who are not on an ACE inhibitor, to reduce the risk of death from cardiovascular causes and reduce HF hospitalization based on the CHARM-Alternative trial.

Speaking for AstraZeneca at the meeting, John McMurray, M.D., the principal investigator of CHARM-Added, said that 96% of the patients in the trial were taking an “individualized, optimum” dose of an ACE inhibitor at baseline, and about 80% of patients were on one of five ACE inhibitors that were considered preferred because of randomized controlled outcome studies of these drugs, said Dr. McMurray, professor of medical cardiology, Western Infirmary, Glasgow, Scotland.

Speaking on the study's efficacy for AstraZeneca, Marc Pfeffer, M.D., interim chair of medicine at Brigham and Women's Hospital, Boston, and cochair of the CHARM executive committee, said that in CHARM-Added, there was there was no evidence that the beneficial effect of candesartan on cardiovascular death or HF hospitalization, was modified “based on ACE inhibitor dose or choice of ACE inhibitor.”

James Hainer, M.D., senior director of clinical research at AstraZeneca, said that as expected, due to a greater degree of renin-angiotensin-aldosterone system inhibition, rates of hypotension, abnormal renal function, and hyperkalemia were greater with candesartan. However, these adverse events did not translate into any increases in all-cause hospitalization and/or mortality, sudden death, renal failure, or ventricular fibrillation, he said.

These risks will be addressed on the label in warnings and precautions about hypotension, renal dysfunction, and hyperkalemia and recommendations for monitoring and reducing risk, and through interactions with major societies and treatment guidelines committees, he said.

Dr. McMurray said that on balance, the risk was “substantially” in favor of candesartan: A cost analysis found that for every 1,000 patients treated with candesartan, there were 1,900 fewer days spent in the hospital for worsening heart failure, he told the panel.

ROCKVILLE, MD. — The angiotensin receptor blocker candesartan should be approved as a treatment for heart failure in patients who are on an ACE inhibitor, a Food and Drug Administration advisory panel has unanimously recommended.

The FDA's cardiovascular and renal drugs advisory committee backed the approval on the basis of results of one of the three Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials.

In CHARM-Added, candesartan (titrated to a target dose of 32 mg/day) was compared with placebo in 2,548 patients with New York Heart Association (NYHA) class II-IV heart failure (HF) and a left ventricular ejection fraction (LVEF) at or below 40% who were on an ACE inhibitor and standard therapy. The results showed that adding an ARB to standard treatment that included an ACE inhibitor added an incremental benefit in this population: The relative risk of cardiovascular mortality or HF hospitalization—the primary end point—was reduced by 15% in those on candesartan during a median follow-up of 41 months. The benefits were also seen in patients treated with β-blockers, which suggested no adverse interactions among β-blockers, candesartan, and ACE inhibitors, as was noted in the Valsartan Heart Failure Trial (Val-HeFT), in which HF morbidity was worse in patients on an ACE inhibitor, β-blocker, and valsartan, according to the FDA.

The purpose of the panel meeting was to determine, according to the FDA's agenda, “whether CHARM-Added provides compelling evidence that candesartan should, under some circumstances, be recommended for use in patients on an ACE inhibitor.”

But a large portion of the meeting was spent discussing whether patients in the trial were on optimal ACE inhibitor doses and whether the same benefits might have been achieved by increasing the dose of the ACE inhibitor.

Although panelists said a forced titration of ACE inhibitor therapy in the study protocol would have been ideal, they said they felt comfortable that the ACE inhibitor doses used fell into the ranges considered adequate or optimal. The “final doses of ACE inhibitor achieved were quite substantial” and in line with the doses seen in other trials of ACE inhibitor therapy, said Blasé Carabello, M.D., professor of medicine at Baylor University, Houston. In addition, an analysis of a subset of patients on high doses of ACE inhibitors “all go in the same direction” favoring the benefit.

The FDA usually follows the recommendations of its advisory panels, which are made up of outside experts. If approved, candesartan (marketed as Atacand by AstraZeneca Pharmaceuticals LP) will be the first ARB approved for use with an ACE inhibitor. Shortly before the panel meeting, the agency approved candesartan for patients with NYHA class II-IV heart failure, and an LVEF at or below 40%, who are not on an ACE inhibitor, to reduce the risk of death from cardiovascular causes and reduce HF hospitalization based on the CHARM-Alternative trial.

Speaking for AstraZeneca at the meeting, John McMurray, M.D., the principal investigator of CHARM-Added, said that 96% of the patients in the trial were taking an “individualized, optimum” dose of an ACE inhibitor at baseline, and about 80% of patients were on one of five ACE inhibitors that were considered preferred because of randomized controlled outcome studies of these drugs, said Dr. McMurray, professor of medical cardiology, Western Infirmary, Glasgow, Scotland.

Speaking on the study's efficacy for AstraZeneca, Marc Pfeffer, M.D., interim chair of medicine at Brigham and Women's Hospital, Boston, and cochair of the CHARM executive committee, said that in CHARM-Added, there was there was no evidence that the beneficial effect of candesartan on cardiovascular death or HF hospitalization, was modified “based on ACE inhibitor dose or choice of ACE inhibitor.”

James Hainer, M.D., senior director of clinical research at AstraZeneca, said that as expected, due to a greater degree of renin-angiotensin-aldosterone system inhibition, rates of hypotension, abnormal renal function, and hyperkalemia were greater with candesartan. However, these adverse events did not translate into any increases in all-cause hospitalization and/or mortality, sudden death, renal failure, or ventricular fibrillation, he said.

These risks will be addressed on the label in warnings and precautions about hypotension, renal dysfunction, and hyperkalemia and recommendations for monitoring and reducing risk, and through interactions with major societies and treatment guidelines committees, he said.

Dr. McMurray said that on balance, the risk was “substantially” in favor of candesartan: A cost analysis found that for every 1,000 patients treated with candesartan, there were 1,900 fewer days spent in the hospital for worsening heart failure, he told the panel.

The recent approval of candesartan for a heart failure indication reflects the key findings of one of the three international trials comparing candesartan with placebo in patients with heart failure.

In February, the Food and Drug Administration approved the angiotensin receptor blocker (ARB) for treating patients with heart failure (New York Heart Association class II or IV and a left ventricular ejection fraction [LVEF] of 40% or less), “to reduce the risk of death from cardiovascular causes and to reduce hospitalizations for heart failure.” In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial, the risk of cardiovascular death or hospitalization for heart failure, the primary end point, was reduced by 23% among those on candesartan after a median follow-up of 34 months, compared with those on placebo—a highly statistically significant effect.

This trial, one of three in the CHARM program, enrolled 2,028 patients with symptomatic heart failure and an LVEF less than or equal to 40%, who were on standard heart failure treatments but were intolerant of ACE inhibitors. At baseline, 85% were on diuretics, 46% on digoxin, 55% on β-blockers, and 24% on spironolactone. There were 334 events in the 1,013 patients on candesartan, vs. 406 events in the 1,015 on placebo.

Supporting the approval of this indication, according to the FDA, were the results of CHARM-Added, which enrolled more than 2,500 patients with NYHA class II-IV heart failure and LVEFs at or below 40% who were on an ACE inhibitor. In this trial, adding candesartan to standard treatment, including a β-blocker, reduced the risk of cardiovascular mortality by 15%, compared with placebo, and significantly improved in heart failure symptoms, as assessed by NYHA functional class.

An approval for use in heart failure patients on ACE inhibitors is likely to follow. (See accompanying story.)

Candesartan, marketed as Atacand by AstraZeneca Pharmaceuticals LP, is the second ARB approved for heart failure; the first was Diovan (valsartan), approved in 2002 for a narrower indication, NYHA class II-IV heart failure in people who cannot tolerate ACE inhibitors. Candesartan was approved for hypertension in 1998.

Using candesartan for these indications will provide an important new tool for treating heart failure, said Christopher Granger, M.D., CHARM-Alternative's principal investigator, in an interview.

In the CHARM program, 4% of those on candesartan had to stop treatment with the drug because of hypotension, versus 2% of those on placebo. Hyperkalemia leading to discontinuation occurred in 2.4% of those on candesartan, versus 0.6% of those on placebo.

The recommended starting dosage is 4 mg/day, with a target dosage of 32 mg once daily, achieved by doubling the dose approximately every 2 weeks, as tolerated, according to the package insert.

Patients need to be monitored closely when the drug is being titrated because some will develop renal insufficiency, hyperkalemia, or hypotension during titration, side effects expected with any drug that affects the renal angiotensin system, said Dr. Granger, who is director of the cardiac care unit at Duke University, Durham, N.C. In the CHARM trials, it was recommended that investigators check serum potassium and creatinine approximately 2 weeks after dose titration.

Dr. Granger was on the executive committee for CHARM and was a consultant to AstraZeneca for this FDA approval and for the meeting of the FDA's cardiovascular and renal drugs advisory committee.

The recent approval of candesartan for a heart failure indication reflects the key findings of one of the three international trials comparing candesartan with placebo in patients with heart failure.

In February, the Food and Drug Administration approved the angiotensin receptor blocker (ARB) for treating patients with heart failure (New York Heart Association class II or IV and a left ventricular ejection fraction [LVEF] of 40% or less), “to reduce the risk of death from cardiovascular causes and to reduce hospitalizations for heart failure.” In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial, the risk of cardiovascular death or hospitalization for heart failure, the primary end point, was reduced by 23% among those on candesartan after a median follow-up of 34 months, compared with those on placebo—a highly statistically significant effect.

This trial, one of three in the CHARM program, enrolled 2,028 patients with symptomatic heart failure and an LVEF less than or equal to 40%, who were on standard heart failure treatments but were intolerant of ACE inhibitors. At baseline, 85% were on diuretics, 46% on digoxin, 55% on β-blockers, and 24% on spironolactone. There were 334 events in the 1,013 patients on candesartan, vs. 406 events in the 1,015 on placebo.

Supporting the approval of this indication, according to the FDA, were the results of CHARM-Added, which enrolled more than 2,500 patients with NYHA class II-IV heart failure and LVEFs at or below 40% who were on an ACE inhibitor. In this trial, adding candesartan to standard treatment, including a β-blocker, reduced the risk of cardiovascular mortality by 15%, compared with placebo, and significantly improved in heart failure symptoms, as assessed by NYHA functional class.

An approval for use in heart failure patients on ACE inhibitors is likely to follow. (See accompanying story.)

Candesartan, marketed as Atacand by AstraZeneca Pharmaceuticals LP, is the second ARB approved for heart failure; the first was Diovan (valsartan), approved in 2002 for a narrower indication, NYHA class II-IV heart failure in people who cannot tolerate ACE inhibitors. Candesartan was approved for hypertension in 1998.

Using candesartan for these indications will provide an important new tool for treating heart failure, said Christopher Granger, M.D., CHARM-Alternative's principal investigator, in an interview.

In the CHARM program, 4% of those on candesartan had to stop treatment with the drug because of hypotension, versus 2% of those on placebo. Hyperkalemia leading to discontinuation occurred in 2.4% of those on candesartan, versus 0.6% of those on placebo.

The recommended starting dosage is 4 mg/day, with a target dosage of 32 mg once daily, achieved by doubling the dose approximately every 2 weeks, as tolerated, according to the package insert.

Patients need to be monitored closely when the drug is being titrated because some will develop renal insufficiency, hyperkalemia, or hypotension during titration, side effects expected with any drug that affects the renal angiotensin system, said Dr. Granger, who is director of the cardiac care unit at Duke University, Durham, N.C. In the CHARM trials, it was recommended that investigators check serum potassium and creatinine approximately 2 weeks after dose titration.

Dr. Granger was on the executive committee for CHARM and was a consultant to AstraZeneca for this FDA approval and for the meeting of the FDA's cardiovascular and renal drugs advisory committee.

The recent approval of candesartan for a heart failure indication reflects the key findings of one of the three international trials comparing candesartan with placebo in patients with heart failure.

In February, the Food and Drug Administration approved the angiotensin receptor blocker (ARB) for treating patients with heart failure (New York Heart Association class II or IV and a left ventricular ejection fraction [LVEF] of 40% or less), “to reduce the risk of death from cardiovascular causes and to reduce hospitalizations for heart failure.” In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial, the risk of cardiovascular death or hospitalization for heart failure, the primary end point, was reduced by 23% among those on candesartan after a median follow-up of 34 months, compared with those on placebo—a highly statistically significant effect.

This trial, one of three in the CHARM program, enrolled 2,028 patients with symptomatic heart failure and an LVEF less than or equal to 40%, who were on standard heart failure treatments but were intolerant of ACE inhibitors. At baseline, 85% were on diuretics, 46% on digoxin, 55% on β-blockers, and 24% on spironolactone. There were 334 events in the 1,013 patients on candesartan, vs. 406 events in the 1,015 on placebo.

Supporting the approval of this indication, according to the FDA, were the results of CHARM-Added, which enrolled more than 2,500 patients with NYHA class II-IV heart failure and LVEFs at or below 40% who were on an ACE inhibitor. In this trial, adding candesartan to standard treatment, including a β-blocker, reduced the risk of cardiovascular mortality by 15%, compared with placebo, and significantly improved in heart failure symptoms, as assessed by NYHA functional class.

An approval for use in heart failure patients on ACE inhibitors is likely to follow. (See accompanying story.)

Candesartan, marketed as Atacand by AstraZeneca Pharmaceuticals LP, is the second ARB approved for heart failure; the first was Diovan (valsartan), approved in 2002 for a narrower indication, NYHA class II-IV heart failure in people who cannot tolerate ACE inhibitors. Candesartan was approved for hypertension in 1998.

Using candesartan for these indications will provide an important new tool for treating heart failure, said Christopher Granger, M.D., CHARM-Alternative's principal investigator, in an interview.

In the CHARM program, 4% of those on candesartan had to stop treatment with the drug because of hypotension, versus 2% of those on placebo. Hyperkalemia leading to discontinuation occurred in 2.4% of those on candesartan, versus 0.6% of those on placebo.

The recommended starting dosage is 4 mg/day, with a target dosage of 32 mg once daily, achieved by doubling the dose approximately every 2 weeks, as tolerated, according to the package insert.

Patients need to be monitored closely when the drug is being titrated because some will develop renal insufficiency, hyperkalemia, or hypotension during titration, side effects expected with any drug that affects the renal angiotensin system, said Dr. Granger, who is director of the cardiac care unit at Duke University, Durham, N.C. In the CHARM trials, it was recommended that investigators check serum potassium and creatinine approximately 2 weeks after dose titration.

Dr. Granger was on the executive committee for CHARM and was a consultant to AstraZeneca for this FDA approval and for the meeting of the FDA's cardiovascular and renal drugs advisory committee.

GAITHERSBURG, MD. — Entecavir, an oral antiviral drug that has several advantages over currently available treatments for chronic hepatitis B, should be studied in pediatric populations, a Food and Drug Administration advisory panel recommended.

At a meeting of the FDA's Antiviral Drugs Advisory Committee last month, held primarily to review the safety and efficacy of the drug in adults, panel members recommended that the manufacturer, Bristol-Myers Squibb Co., conduct phase I and pharmacokinetic studies in children, and carcinogenicity studies in young animals.

The panel discussed potential use of entecavir—a nucleoside analogue that is a potent, selective inhibitor of hepatitis B virus (HBV) replication—in pediatric patients after unanimously agreeing (18-0) that the risk-benefit appraisal of the drug supported its approval for treating chronic HBV infections in adults. The drug was approved for adults last month within weeks of the panel meeting.

Despite concerns about a theoretical risk of malignancies in humans, the panel cited the very real risk of hepatocellular carcinoma associated with chronic HBV, safety and effectiveness data in 48-week trials of more than 1,000 patients who were either treatment naïve or refractory to lamivudine, and the lack of significant evidence of resistance to date.

In preclinical studies, the incidence of lung tumors and other malignancies was increased significantly in rodents exposed to entecavir, mostly at very high doses. To date, however, no increase in malignancies has been detected in clinical trials. Because of these findings, the FDA had asked the manufacturer to delay pediatric trials.

It would be an “enormous benefit” to have a safe and effective drug for pediatric HBV, remarked Kathleen Schwarz, M.D., director of the division of pediatric gastroenterology and nutrition, Johns Hopkins University, Baltimore. She added that more data about the carcinogenicity potential of entecavir and the effect of long-term exposure on the injured liver were needed. She recommended studies of the drug in young animals, particularly primates.

Interferon, which is administered subcutaneously, is approved for treating hepatitis B in children aged 1 and older, but its side effects are problematic. Lamivudine (Epivir), a nucleoside analogue that is taken orally, is approved for children aged 3 and older, but the rate of lamivudine resistance is about 20% with 1 year of treatment, said Dr. Schwarz, a voting consultant to the panel. Pediatric trials of the third drug approved for HBV in the United States, adefovir dipivoxil, a nucleotide analogue that is active against lamivudine-resistant virus, are underway, she noted.

Because Bristol-Myers Squibb plans to market an oral solution, once entecavir is approved, it will immediately be used off label in children, she and others on the panel predicted. (The oral solution is intended to help with dosing issues in adult patients who have renal insufficiency.)

Dr. Schwarz and other pediatricians on the panel said they were concerned that entecavir would be used inappropriately in pediatric patients once approved, before the appropriate studies were completed. The panel chair, Janet Englund, M.D., of the division of infectious diseases at Children's Hospital and Regional Medical Center, Seattle, noted that how to dose children was not yet known. Lauren Wood, M.D., senior clinical investigator in the HIV and AIDS malignancy branch of the National Cancer Institute, Bethesda, Md., pointed out that a drug's safety and efficacy can differ greatly in children, citing an example of an HIV drug that caused bone toxicity in children, but not in adults.

Mostly urban adolescents and international adoptees in the United States are infected with HBV, and children around the world have perinatally-acquired HBV, she said. Babies with perinatally-acquired HBV have a high lifetime risk of hepatocellular carcinoma, as high as 40% in some studies, added Dr. Schwarz. And there also is a significant social stigma associated with having hepatitis B, including in young children.

The FDA usually follows the advice of these panels, which is not binding. If the drug is approved, Bristol-Myers Squibb will market entecavir under the trade name Baraclude. Approval could be imminent, because the drug is under a priority review, but had not yet been announced at press time.

The three phase III adult studies compared entecavir with lamivudine in more than 1,500 adults with chronic HBV infections and active liver inflammation, including HBeAg-negative and HBeAg-positive patients who had not been treated with a nucleoside, and HBeAg-positive patients who were refractory to lamivudine. In all three groups, a significantly greater proportion of those treated with entecavir than of those treated with lamivudine met the primary end point, histologic improvement in liver biopsy after 48 weeks of treatment. In all three groups, the mean reduction in HBV DNA was significantly greater among those treated with entecavir, and significantly more patients on entecavir had normalization of ALT levels than did those treated with lamivudine.

The safety profiles and malignancy rates were comparable in the entecavir and lamivudine-treated groups, according to the company. Entecavir also has a favorable resistance profile compared with lamivudine, according to Bristol-Myers Squibb.

During the discussion on adult use, Leonard Seeff, M.D., senior scientist for hepatitis research at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., said there was “no question” that entecavir is very effective at reducing viral load. “We need other treatments, and this drug has advantages that others don't—namely, at least at this point, a lower rate of mutant strains developing and no nephrotoxicity,” he remarked.

Bristol-Myers Squibb has proposed a pharmacovigilance study that would aim to enroll 12,500 patients worldwide, randomize them to entecavir or another HBV drug treatment, and follow them for malignancies and progression of liver disease for 5-8 years. The panel agreed that the trial would be critical in determining whether the drug's malignancy risk would increase, and whether resistant strains would develop with a longer duration of treatment.

GAITHERSBURG, MD. — Entecavir, an oral antiviral drug that has several advantages over currently available treatments for chronic hepatitis B, should be studied in pediatric populations, a Food and Drug Administration advisory panel recommended.

At a meeting of the FDA's Antiviral Drugs Advisory Committee last month, held primarily to review the safety and efficacy of the drug in adults, panel members recommended that the manufacturer, Bristol-Myers Squibb Co., conduct phase I and pharmacokinetic studies in children, and carcinogenicity studies in young animals.

The panel discussed potential use of entecavir—a nucleoside analogue that is a potent, selective inhibitor of hepatitis B virus (HBV) replication—in pediatric patients after unanimously agreeing (18-0) that the risk-benefit appraisal of the drug supported its approval for treating chronic HBV infections in adults. The drug was approved for adults last month within weeks of the panel meeting.

Despite concerns about a theoretical risk of malignancies in humans, the panel cited the very real risk of hepatocellular carcinoma associated with chronic HBV, safety and effectiveness data in 48-week trials of more than 1,000 patients who were either treatment naïve or refractory to lamivudine, and the lack of significant evidence of resistance to date.

In preclinical studies, the incidence of lung tumors and other malignancies was increased significantly in rodents exposed to entecavir, mostly at very high doses. To date, however, no increase in malignancies has been detected in clinical trials. Because of these findings, the FDA had asked the manufacturer to delay pediatric trials.

It would be an “enormous benefit” to have a safe and effective drug for pediatric HBV, remarked Kathleen Schwarz, M.D., director of the division of pediatric gastroenterology and nutrition, Johns Hopkins University, Baltimore. She added that more data about the carcinogenicity potential of entecavir and the effect of long-term exposure on the injured liver were needed. She recommended studies of the drug in young animals, particularly primates.

Interferon, which is administered subcutaneously, is approved for treating hepatitis B in children aged 1 and older, but its side effects are problematic. Lamivudine (Epivir), a nucleoside analogue that is taken orally, is approved for children aged 3 and older, but the rate of lamivudine resistance is about 20% with 1 year of treatment, said Dr. Schwarz, a voting consultant to the panel. Pediatric trials of the third drug approved for HBV in the United States, adefovir dipivoxil, a nucleotide analogue that is active against lamivudine-resistant virus, are underway, she noted.

Because Bristol-Myers Squibb plans to market an oral solution, once entecavir is approved, it will immediately be used off label in children, she and others on the panel predicted. (The oral solution is intended to help with dosing issues in adult patients who have renal insufficiency.)

Dr. Schwarz and other pediatricians on the panel said they were concerned that entecavir would be used inappropriately in pediatric patients once approved, before the appropriate studies were completed. The panel chair, Janet Englund, M.D., of the division of infectious diseases at Children's Hospital and Regional Medical Center, Seattle, noted that how to dose children was not yet known. Lauren Wood, M.D., senior clinical investigator in the HIV and AIDS malignancy branch of the National Cancer Institute, Bethesda, Md., pointed out that a drug's safety and efficacy can differ greatly in children, citing an example of an HIV drug that caused bone toxicity in children, but not in adults.

Mostly urban adolescents and international adoptees in the United States are infected with HBV, and children around the world have perinatally-acquired HBV, she said. Babies with perinatally-acquired HBV have a high lifetime risk of hepatocellular carcinoma, as high as 40% in some studies, added Dr. Schwarz. And there also is a significant social stigma associated with having hepatitis B, including in young children.

The FDA usually follows the advice of these panels, which is not binding. If the drug is approved, Bristol-Myers Squibb will market entecavir under the trade name Baraclude. Approval could be imminent, because the drug is under a priority review, but had not yet been announced at press time.

The three phase III adult studies compared entecavir with lamivudine in more than 1,500 adults with chronic HBV infections and active liver inflammation, including HBeAg-negative and HBeAg-positive patients who had not been treated with a nucleoside, and HBeAg-positive patients who were refractory to lamivudine. In all three groups, a significantly greater proportion of those treated with entecavir than of those treated with lamivudine met the primary end point, histologic improvement in liver biopsy after 48 weeks of treatment. In all three groups, the mean reduction in HBV DNA was significantly greater among those treated with entecavir, and significantly more patients on entecavir had normalization of ALT levels than did those treated with lamivudine.

The safety profiles and malignancy rates were comparable in the entecavir and lamivudine-treated groups, according to the company. Entecavir also has a favorable resistance profile compared with lamivudine, according to Bristol-Myers Squibb.

During the discussion on adult use, Leonard Seeff, M.D., senior scientist for hepatitis research at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., said there was “no question” that entecavir is very effective at reducing viral load. “We need other treatments, and this drug has advantages that others don't—namely, at least at this point, a lower rate of mutant strains developing and no nephrotoxicity,” he remarked.

Bristol-Myers Squibb has proposed a pharmacovigilance study that would aim to enroll 12,500 patients worldwide, randomize them to entecavir or another HBV drug treatment, and follow them for malignancies and progression of liver disease for 5-8 years. The panel agreed that the trial would be critical in determining whether the drug's malignancy risk would increase, and whether resistant strains would develop with a longer duration of treatment.

GAITHERSBURG, MD. — Entecavir, an oral antiviral drug that has several advantages over currently available treatments for chronic hepatitis B, should be studied in pediatric populations, a Food and Drug Administration advisory panel recommended.

At a meeting of the FDA's Antiviral Drugs Advisory Committee last month, held primarily to review the safety and efficacy of the drug in adults, panel members recommended that the manufacturer, Bristol-Myers Squibb Co., conduct phase I and pharmacokinetic studies in children, and carcinogenicity studies in young animals.

The panel discussed potential use of entecavir—a nucleoside analogue that is a potent, selective inhibitor of hepatitis B virus (HBV) replication—in pediatric patients after unanimously agreeing (18-0) that the risk-benefit appraisal of the drug supported its approval for treating chronic HBV infections in adults. The drug was approved for adults last month within weeks of the panel meeting.

Despite concerns about a theoretical risk of malignancies in humans, the panel cited the very real risk of hepatocellular carcinoma associated with chronic HBV, safety and effectiveness data in 48-week trials of more than 1,000 patients who were either treatment naïve or refractory to lamivudine, and the lack of significant evidence of resistance to date.

In preclinical studies, the incidence of lung tumors and other malignancies was increased significantly in rodents exposed to entecavir, mostly at very high doses. To date, however, no increase in malignancies has been detected in clinical trials. Because of these findings, the FDA had asked the manufacturer to delay pediatric trials.

It would be an “enormous benefit” to have a safe and effective drug for pediatric HBV, remarked Kathleen Schwarz, M.D., director of the division of pediatric gastroenterology and nutrition, Johns Hopkins University, Baltimore. She added that more data about the carcinogenicity potential of entecavir and the effect of long-term exposure on the injured liver were needed. She recommended studies of the drug in young animals, particularly primates.

Interferon, which is administered subcutaneously, is approved for treating hepatitis B in children aged 1 and older, but its side effects are problematic. Lamivudine (Epivir), a nucleoside analogue that is taken orally, is approved for children aged 3 and older, but the rate of lamivudine resistance is about 20% with 1 year of treatment, said Dr. Schwarz, a voting consultant to the panel. Pediatric trials of the third drug approved for HBV in the United States, adefovir dipivoxil, a nucleotide analogue that is active against lamivudine-resistant virus, are underway, she noted.

Because Bristol-Myers Squibb plans to market an oral solution, once entecavir is approved, it will immediately be used off label in children, she and others on the panel predicted. (The oral solution is intended to help with dosing issues in adult patients who have renal insufficiency.)

Dr. Schwarz and other pediatricians on the panel said they were concerned that entecavir would be used inappropriately in pediatric patients once approved, before the appropriate studies were completed. The panel chair, Janet Englund, M.D., of the division of infectious diseases at Children's Hospital and Regional Medical Center, Seattle, noted that how to dose children was not yet known. Lauren Wood, M.D., senior clinical investigator in the HIV and AIDS malignancy branch of the National Cancer Institute, Bethesda, Md., pointed out that a drug's safety and efficacy can differ greatly in children, citing an example of an HIV drug that caused bone toxicity in children, but not in adults.

Mostly urban adolescents and international adoptees in the United States are infected with HBV, and children around the world have perinatally-acquired HBV, she said. Babies with perinatally-acquired HBV have a high lifetime risk of hepatocellular carcinoma, as high as 40% in some studies, added Dr. Schwarz. And there also is a significant social stigma associated with having hepatitis B, including in young children.

The FDA usually follows the advice of these panels, which is not binding. If the drug is approved, Bristol-Myers Squibb will market entecavir under the trade name Baraclude. Approval could be imminent, because the drug is under a priority review, but had not yet been announced at press time.

The three phase III adult studies compared entecavir with lamivudine in more than 1,500 adults with chronic HBV infections and active liver inflammation, including HBeAg-negative and HBeAg-positive patients who had not been treated with a nucleoside, and HBeAg-positive patients who were refractory to lamivudine. In all three groups, a significantly greater proportion of those treated with entecavir than of those treated with lamivudine met the primary end point, histologic improvement in liver biopsy after 48 weeks of treatment. In all three groups, the mean reduction in HBV DNA was significantly greater among those treated with entecavir, and significantly more patients on entecavir had normalization of ALT levels than did those treated with lamivudine.

The safety profiles and malignancy rates were comparable in the entecavir and lamivudine-treated groups, according to the company. Entecavir also has a favorable resistance profile compared with lamivudine, according to Bristol-Myers Squibb.

During the discussion on adult use, Leonard Seeff, M.D., senior scientist for hepatitis research at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., said there was “no question” that entecavir is very effective at reducing viral load. “We need other treatments, and this drug has advantages that others don't—namely, at least at this point, a lower rate of mutant strains developing and no nephrotoxicity,” he remarked.

Bristol-Myers Squibb has proposed a pharmacovigilance study that would aim to enroll 12,500 patients worldwide, randomize them to entecavir or another HBV drug treatment, and follow them for malignancies and progression of liver disease for 5-8 years. The panel agreed that the trial would be critical in determining whether the drug's malignancy risk would increase, and whether resistant strains would develop with a longer duration of treatment.